Pteridinone compounds and uses thereof

ABSTRACT

The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof for treating cellular proliferative disorders (e.g., cancer).

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jul. 23, 2019, isnamed 394927-020WO_SL.txt and is 788 bytes in size.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful fortreating cellular proliferative disorders (e.g., cancer). The inventionalso provides pharmaceutically acceptable compositions comprisingcompounds of the present invention and methods of using saidcompositions in the treatment of various proliferative disorders.

BACKGROUND OF THE INVENTION

Cellular proliferative disorders comprise malignant and non-malignantcell populations which differ from the surround tissue morphologicallyand/or genotypically. Examples of cellular proliferative disordersinclude, for example, solid tumors, cancer, diabetic retinopathy,intraocular neovascular syndromes, macular degeneration, rheumatoidarthritis, psoriasis, and endometriosis. Cancer is a group of diseasesinvolving abnormal cell proliferation with the potential to invade orspread to other parts of the body. According to Centers for DiseaseControl and Prevention (CDC), Cancer is the second leading cause ofdeath in the United States. Therefore, additional treatments forcellular proliferative disorders are desired to provide patients withmore options.

SUMMARY OF THE INVENTION

It has now been found that compounds of the present invention, andpharmaceutically acceptable compositions thereof, are useful fortreating proliferative disorders (e.g., cancer). In one aspect, thepresent invention provides a compound of Formula I.

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of proliferativedisorders (e.g., cancer) as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the effect of Compound 136 on severaltranscriptional reporters and shows the fold change in reporter activity(p<0.01) in HepG2 cells treated with 1 μM of Compound 136 for six hours.

FIG. 2 is an immunoblot showing the WFS1 and tubulin protein levels inparental HepG2 cells and HepG2 cells where WFS1 is knocked out byCRISPR/Cas9.

FIG. 3 is an immunoblot showing the WFS1 protein levels in Hek293 cellstransduced with an empty control retrovirus (pCLPCX) and Hek293 cellstransduced with a retrovirus encoding the full length WFS1 cDNA.

FIG. 4 is an immunoblot showing WFS1 and tubulin protein levels in HepG2and DU4475 cancer cells expressing either negative control shRNA orshRNA targeting WFS1.

FIG. 5A is a graph showing the degree of calcium flux induced byCompound 136 in HepG2 cells, where levels of WFS1 protein have beenaltered by either knockout (KO) or over-expression.

FIG. 5B is a graph showing the degree of calcium flux induced byCompound 136 in Hek293 cells, where levels of WFS1 protein have beenaltered by either knockout (KO) or over-expression.

FIG. 6 is an immunoblot showing WFS1, ATF4, XBP1(s), lamin, and tubulinprotein levels in either parental HepG2 cells or HepG2 cells where WFS1is knocked out by CRISPR/Cas9 after 6 hours of exposure to eitherCompound 136 or thapsigargin.

FIG. 7 is a graph depicting the number of genes whose expression changesmore than 2 fold in either parental HepG2 cells or HepG2 cells whereWFS1 is knocked out by CRISPR/Cas9 after 6 hours of exposure to eitherCompound 136 or thapsigargin.

FIG. 8 is a graph showing the degree of binding of radiolabeled Compound136 to membrane lysates from cells with varying degrees of WFS1 proteinexpression.

FIG. 9 is a graph showing association between WFS1 gene expression andresponse to Compound 136 in a panel of bladder cancer cell lines.

FIG. 10 is a graph showing association between WFS1 gene expression andresponse to Compound 136 in a panel of 428 cancer cell lines.

FIG. 11 is a graph showing association between WFS1 gene expression andresponse to Compound 136 in a panel of 23 patient-derived lungxenografts.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

It has been found that the compounds of the present invention, or saltsthereof, exhibit pronounced efficacy in multiple cell-line-derived andpatient-derived xenograft models. For example, the compounds of theinvention, or salts thereof, are found to lead to complete and durableregression in models of non-small cell lung cancer (NSCLC), myeloma,hepatocellular carcinoma (HCC), breast cancer, and melanoma. It has alsobeen found that the compounds of the invention result in enhancedinhibition of cell viability, particularly the cells where Wolframin(WFS1) is overexpressed. Without wishing to be bound by any specifictheory, it is believed that the compounds of the invention cause calciumrelease from the endoplasmic reticulum (ER) via a putative Ca²⁺ channelknown as Wolframin (WFS1), which induces ER stress and the “unfoldedprotein response” (UPR) and leads to cell death.

In one aspect, the present invention provides a compound of formula I.

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, indanyl, a 4-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 8-12 membered saturated or partially    unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5-8    membered saturated or partially unsaturated bridged bicyclic    carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   L is a covalent bond or a C₁₋₆ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein one to three    methylene units of the chain are independently and optionally    replaced with -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—, —CR(OR)—,    —C(D)₂-, —C(F)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—,    —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—,    —OC(O)—, —C(O)O—, —S—, —S(O)—, —S(O)₂—, or —Si(R)₂—, wherein -Cy- is    an optionally substituted bivalent group selected from phenylenyl,    cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl,    furylenyl, tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl,    piperidylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl,    pyridylenyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or    thiazolylenyl;-   R¹ is hydrogen, R^(D), or an optionally substituted group selected    from C₁₋₃ aliphatic or a 4-8 membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   each of R² and R^(2′) is independently hydrogen, R^(D), or an    optionally substituted group selected from C₁₋₆ aliphatic, a 3-8    membered saturated or partially unsaturated monocyclic carbocyclic    ring, a 4-8 membered saturated or partially unsaturated monocyclic    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic    heteroaromatic ring having 1-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur; or    -   R² and R^(2′) are optionally taken together to form ═CH₂ or        ═CH—(C₁₋₃ aliphatic); or    -   R² and R^(2′) are optionally taken together with their        intervening atoms to form an optionally substituted 3-6 membered        saturated or partially unsaturated spirocyclic ring having 0-2        heteroatoms independently selected from nitrogen, oxygen or        sulfur;-   R³ is hydrogen, R^(D), or an optionally substituted C₁₋₆ aliphatic    group; or-   R² and R³ are optionally taken together with their intervening atoms    to form an optionally substituted 5-8 membered saturated or    partially unsaturated fused ring comprising the nitrogen atom to    which R³ attaches and 0-2 additional heteroatoms independently    selected from nitrogen, oxygen or sulfur; or-   R², R^(2′), and R³ are optionally taken together with their    intervening atoms to form an optionally substituted 5-8 membered    saturated or partially unsaturated fused ring comprising the    nitrogen atom to which R³ attaches and 0-2 additional heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   R⁴ is hydrogen, R^(D), —CD₂OH, or an optionally substituted C₁₋₃    aliphatic group;-   R⁵ is hydrogen, —C(O)R, —C(O)OR, —C(O)NR₂, an optionally substituted    3-8 membered saturated or partially unsaturated monocyclic    carbocyclic ring, or a C₁₋₃ aliphatic group;-   each of R⁶ is independently halogen, —CN, —NO₂, —C(O)R, —C(O)OR,    —C(O)NR₂, —NR₂, —NRC(O)R, —NRC(O)OR, —NRS(O)₂R, —OR, —P(O)R₂, —SR,    —SF₅, —S(CF₃)₅, —S(O)R, —S(O)₂R, —S(O)(NH)R, —C(═NR)—OR,    —O—C(═NR)—R, or R; or two R⁶ groups are optionally taken together to    form ═O;-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered    saturated or partially unsaturated monocyclic heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   two R groups on the same nitrogen are optionally taken together with    their intervening atoms to form a 4-7 membered saturated, partially    unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition    to the nitrogen, independently selected from nitrogen, oxygen and    sulfur, optionally substituted with 1-2 oxo groups;-   R^(D) is a C₁₋₄ aliphatic group wherein one or more hydrogens are    replaced by deuterium;-   X is N or CH; and-   n is 0, 1, 2, 3, 4 or 5.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bicyclic ring” or “bicyclic ring system”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or having one or more units of unsaturation, having one ormore atoms in common between the two rings of the ring system. Thus, theterm includes any permissible ring fusion, such as ortho-fused orspirocyclic. As used herein, the term “heterobicyclic” is a subset of“bicyclic” that requires that one or more heteroatoms are present in oneor both rings of the bicycle. Such heteroatoms may be present at ringjunctions and are optionally substituted, and may be selected fromnitrogen (including N-oxides), oxygen, sulfur (including oxidized formssuch as sulfones and sulfonates), phosphorus (including oxidized formssuch as phosphates), boron, etc. In some embodiments, a bicyclic grouphas 7-12 ring members and 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic”refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic,saturated or partially unsaturated, having at least one bridge. Asdefined by IUPAC, a “bridge” is an unbranched chain of atoms or an atomor a valence bond connecting two bridgeheads, where a “bridgehead” isany skeletal atom of the ring system which is bonded to three or moreskeletal atoms (excluding hydrogen). In some embodiments, a bridgedbicyclic group has 7-12 ring members and 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groupsare well known in the art and include those groups set forth below whereeach group is attached to the rest of the molecule at any substitutablecarbon or nitrogen atom. Unless otherwise specified, a bridged bicyclicgroup is optionally substituted with one or more substituents as setforth for aliphatic groups. Additionally or alternatively, anysubstitutable nitrogen of a bridged bicyclic group is optionallysubstituted. Exemplary bicyclic rings include:

Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Each optional substituent on a substitutable carbon is a monovalentsubstituent independently selected from halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—S(O)(NR^(∘))R^(∘); —S(O)₂N═C(NR^(∘) ₂)₂; —(CH₂)₀₋₄S(O)R^(∘);—N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘); —N(OR^(∘))R^(∘);—C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘2); —OP(O)R^(∘) ₂;—OP(O)(OR^(∘))₂; —SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂.

Each R^(∘) is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted by a divalentsubstituent on a saturated carbon atom of R^(∘) selected from ═O and ═S;or each R^(∘) is optionally substituted with a monovalent substituentindependently selected from halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR′₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•).

Each R^(•) is independently selected from C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, and wherein each R^(•) is unsubstituted or wherepreceded by halo is substituted only with one or more halogens; orwherein an optional substituent on a saturated carbon is a divalentsubstituent independently selected from ═O, ═S, ═NNR*₂, ═NNHC(O)R*,═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, or a divalent substituent bound to vicinalsubstitutable carbons of an “optionally substituted” group is—O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

When R* is C₁₋₆ aliphatic, R* is optionally substituted with halogen,—R*, -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isindependently selected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur, andwherein each R^(•) is unsubstituted or where preceded by halo issubstituted only with one or more halogens.

An optional substituent on a substitutable nitrogen is independently—R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†), —C(O)C(O)R^(†),—C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂, —C(S)NR^(†) ₂,—C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein each R^(†) isindependently hydrogen, C₁₋₆ aliphatic, unsubstituted —OPh, or anunsubstituted 5-6-membered saturated, partially unsaturated, or arylring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, two independent occurrences of R^(†), takentogether with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; wherein when R^(†) is C₁₋₆ aliphatic, R^(†)is optionally substituted with halogen, —R^(•), -(haloR^(•)), —OH,—OR^(•), —O(haloR^(•)), —CN, —C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•),—NR^(•) ₂, or —NO₂, wherein each R^(•) is independently selected fromC₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated,partially unsaturated, or aryl ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, and wherein each R^(•) isunsubstituted or where preceded by halo is substituted only with one ormore halogens.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

3. Description of Exemplary Embodiments

In one aspect, the present invention provides a compound of formula I.

or a pharmaceutically acceptable salt thereof, wherein:

-   Ring A is selected from a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, indanyl, a 4-8    membered saturated or partially unsaturated monocyclic heterocyclic    ring having 1-2 heteroatoms independently selected from nitrogen,    oxygen, or sulfur, a 8-12 membered saturated or partially    unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur, a 5-8    membered saturated or partially unsaturated bridged bicyclic    carbocyclic ring, a 5-6 membered monocyclic heteroaromatic ring    having 1-4 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having    1-5 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   L is a covalent bond or a C₁₋₆ bivalent straight or branched    saturated or unsaturated hydrocarbon chain wherein one to three    methylene units of the chain are independently and optionally    replaced with -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—, —CR(OR)—,    —C(D)₂-, —C(F)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—,    —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—,    —OC(O)—, —C(O)O—, —S—, —S(O)—, —S(O)₂—, or —Si(R)₂—, wherein -Cy- is    an optionally substituted bivalent group selected from phenylenyl,    cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl,    furylenyl, tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl,    piperidylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl,    pyridylenyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or    thiazolylenyl;-   R¹ is hydrogen, R^(D), or an optionally substituted group selected    from C₁₋₃ aliphatic or a 4-8 membered saturated or partially    unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms    independently selected from nitrogen, oxygen, or sulfur;-   each of R² and R^(2′) is independently hydrogen, R^(D), or an    optionally substituted group selected from C₁₋₆ aliphatic, a 3-8    membered saturated or partially unsaturated monocyclic carbocyclic    ring, a 4-8 membered saturated or partially unsaturated monocyclic    heterocyclic ring having 1-2 heteroatoms independently selected from    nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic    heteroaromatic ring having 1-4 heteroatoms independently selected    from nitrogen, oxygen, or sulfur; or    -   R² and R^(2′) are optionally taken together to form ═CH₂ or        ═CH—(C₁₋₃ aliphatic); or    -   R² and R^(2′) are optionally taken together with their        intervening atoms to form an optionally substituted 3-6 membered        saturated or partially unsaturated spirocyclic ring having 0-2        heteroatoms independently selected from nitrogen, oxygen or        sulfur;-   R³ is hydrogen, R^(D), or an optionally substituted C₁₋₆ aliphatic    group; or-   R² and R³ are optionally taken together with their intervening atoms    to form an optionally substituted 5-8 membered saturated or    partially unsaturated fused ring comprising the nitrogen atom to    which R³ attaches and 0-2 additional heteroatoms independently    selected from nitrogen, oxygen or sulfur; or-   R², R^(2′), and R³ are optionally taken together with their    intervening atoms to form an optionally substituted 5-8 membered    saturated or partially unsaturated fused ring comprising the    nitrogen atom to which R³ attaches and 0-2 additional heteroatoms    independently selected from nitrogen, oxygen or sulfur;-   R⁴ is hydrogen, R^(D), —CD₂OH, or an optionally substituted C₁₋₃    aliphatic group;-   R⁵ is hydrogen, —C(O)R, —C(O)OR, —C(O)NR₂, an optionally substituted    3-8 membered saturated or partially unsaturated monocyclic    carbocyclic ring, or a C₁₋₃ aliphatic group;-   each of R⁶ is independently halogen, —CN, —NO₂, —C(O)R, —C(O)OR,    —C(O)NR₂, —NR₂, —NRC(O)R, —NRC(O)OR, —NRS(O)₂R, —OR, —P(O)R₂, —SR,    —SF₅, —S(CF₃)s, —S(O)R, —S(O)₂R, —S(O)(NH)R, —C(═NR)—OR,    —O—C(═NR)—R, or R; or two R⁶ groups are optionally taken together to    form ═O;-   each R is independently hydrogen or an optionally substituted group    selected from C₁₋₆ aliphatic, a 3-8 membered saturated or partially    unsaturated monocyclic carbocyclic ring, phenyl, a 4-8 membered    saturated or partially unsaturated monocyclic heterocyclic ring    having 1-2 heteroatoms independently selected from nitrogen, oxygen,    or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having    1-4 heteroatoms independently selected from nitrogen, oxygen, or    sulfur;-   two R groups on the same nitrogen are optionally taken together with    their intervening atoms to form a 4-7 membered saturated, partially    unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition    to the nitrogen, independently selected from nitrogen, oxygen and    sulfur, optionally substituted with 1-2 oxo groups;-   R^(D) is a C₁₋₄ aliphatic group wherein one or more hydrogens are    replaced by deuterium;-   X is N or CH; and-   n is 0, 1, 2, 3, 4 or 5.

As defined generally above, Ring A is selected from a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring, phenyl,indanyl, a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, a 8-12 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, a 5-8 memberedsaturated or partially unsaturated bridged bicyclic carbocyclic ring, a5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or an 8-10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring A is a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, Ring A isphenyl. In some embodiments, Ring A is indanyl. In some embodiments,Ring A is a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 8-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, Ring A is a 5-8 membered saturated orpartially unsaturated bridged bicyclic carbocyclic ring. In someembodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, Ring A is an 8-10 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring A is a 3 membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, Ring A isa 4 membered saturated or partially unsaturated monocyclic carbocyclicring. In some embodiments, Ring A is a 5 membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, Ring A isa 6 membered saturated or partially unsaturated monocyclic carbocyclicring. In some embodiments, Ring A is a 7 membered saturated or partiallyunsaturated monocyclic carbocyclic ring. In some embodiments, Ring A isan 8 membered saturated or partially unsaturated monocyclic carbocyclicring. In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is a 4 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 5 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, Ring Ais a 6 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 7 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, Ring A is a 8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen or oxygen. In some embodiments, Ring A is a 4-8membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1 heteroatom selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is

In some embodiments, Ring A is:

In some embodiments, Ring A is

In some embodiments, Ring A is a 8 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 9 membered saturated or partially unsaturatedbicyclic heterocyclic ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 10membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, Ring A is a 11 membered saturated orpartially unsaturated bicyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 12 membered saturated or partially unsaturatedbicyclic heterocyclic ring having 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 8-12membered saturated or partially unsaturated bicyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen or oxygen.In some embodiments, Ring A is a 8-12 membered saturated or partiallyunsaturated bicyclic heterocyclic ring having 1 heteroatom selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is a 5 membered saturated or partiallyunsaturated bridged bicyclic carbocyclic ring. In some embodiments, RingA is a 6 membered saturated or partially unsaturated bridged bicycliccarbocyclic ring. In some embodiments, Ring A is a 7 membered saturatedor partially unsaturated bridged bicyclic carbocyclic ring. In someembodiments, Ring A is a 8 membered saturated or partially unsaturatedbridged bicyclic carbocyclic ring. In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is a 5 membered monocyclic heteroaromaticring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. In some embodiments, Ring A is a 6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, Ring Ais a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, Ring A is a 5-6 membered monocyclicheteroaromatic ring having 1 heteroatom selected from nitrogen, oxygen,or sulfur. In some embodiments, Ring A is a 5 membered monocyclicheteroaromatic ring having 1-2 heteroatoms independently selected fromnitrogen or oxygen. In some embodiments, Ring A is a 5 memberedmonocyclic heteroaromatic ring having 1-2 heteroatoms independentlyselected from nitrogen or sulfur. In some embodiments, Ring A is a 6membered monocyclic heteroaromatic ring having 1-2 heteroatomsindependently selected from nitrogen or oxygen. In some embodiments,Ring A is a 6 membered monocyclic heteroaromatic ring having 1-2heteroatoms independently selected from nitrogen or sulfur. In someembodiments, Ring-A is

In some embodiments, Ring A is:

In some embodiments, Ring A is a 8 membered bicyclic heteroaromatic ringhaving 5 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, Ring A is a 9 membered bicyclicheteroaromatic ring having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 10membered bicyclic heteroaromatic ring having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ringhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, Ring A is an 8-10 membered bicyclicheteroaromatic ring having 1-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. In some embodiments, Ring A is an 8-10membered bicyclic heteroaromatic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. In someembodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from:

In some embodiments, Ring A is selected from:

In some embodiments, Ring A is:

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in TablesA-C, below.

As defined generally above, L is a covalent bond or a C₁₋₆ bivalentstraight or branched saturated or unsaturated hydrocarbon chain whereinone to three methylene units of the chain are independently andoptionally replaced with -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—,—CR(OR)—, —C(D)₂-, —C(F)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—,—OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)—, —S(O)₂—, or —Si(R)₂—, wherein -Cy- is anoptionally substituted bivalent group selected from phenylenyl,cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl,furylenyl, tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl,piperidylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl.

In some embodiments, L is a covalent bond. In some embodiments, L is aC₁₋₆ bivalent straight or branched saturated or unsaturated hydrocarbonchain wherein one to three methylene units of the chain areindependently and optionally replaced with -Cy-, —O—, —C(R)₂—, —CH(R)—,—CH(OR)—, —CR(OR)—, —C(D)₂-, —C(F)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—,—N(R)C(O)O—, —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—,—C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, —S(O)₂—, or —Si(R)₂—, wherein-Cy- is an optionally substituted bivalent group selected fromphenylenyl, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl,cyclohexylenyl, furylenyl, tetrahydrofurylenyl, azetidylenyl,pyrrolidylenyl, piperidylenyl, triazolylenyl, pyrrolylenyl,pyrazolylenyl, pyridylenyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl.

In some embodiments, L is a C₁₋₆ bivalent straight or branched saturatedor unsaturated hydrocarbon chain wherein one to two methylene units ofthe chain are independently and optionally replaced with -Cy-, —O—,—C(R)₂—, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D)₂-, —C(F)₂—, —N(R)—,—N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—, —N(R)C(O)N(R)—,—N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—,—S(O)₂—, or —Si(R)₂—, wherein -Cy- is an optionally substituted bivalentgroup selected from phenylenyl, cyclopropylenyl, cyclobutylenyl,cyclopentylenyl, cyclohexylenyl, furylenyl, tetrahydrofurylenyl,azetidylenyl, pyrrolidylenyl, piperidylenyl, triazolylenyl,pyrrolylenyl, pyrazolylenyl, pyridylenyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl.

In some embodiments, L is a C₁₋₆ bivalent straight or branched saturatedor unsaturated hydrocarbon chain wherein one methylene unit of the chainis optionally replaced with -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—,—CR(OR)—, —C(D)₂-, —C(F)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—,—OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—, —OC(O)—,—C(O)O—, —S—, —S(O)—, —S(O)₂—, or —Si(R)₂—, wherein -Cy- is anoptionally substituted bivalent group selected from phenylenyl,cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl,furylenyl, tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl,piperidylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl.

In some embodiments, L is an unsubstituted C₁₋₆ bivalent straight orbranched saturated or unsaturated hydrocarbon chain. In someembodiments, L is —CH₂—. In some embodiments, L is —CH₂CH₂—. In someembodiments, L is —CH₂CH₂CH₂—. In some embodiments, L is —CH₂CH₂CH₂CH₂—.In some embodiments, L is —CH₂CH₂CH₂CH₂CH₂—. In some embodiments, L is—CH₂CH₂CH₂CH₂CH₂CH₂—.

In some embodiments, L is a C₁₋₆ bivalent straight or branched saturatedor unsaturated hydrocarbon chain wherein one methylene unit of the chainis optionally replaced with -Cy-, wherein -Cy- is an optionallysubstituted bivalent group selected from phenylenyl, cyclopropylenyl,cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, furylenyl,tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl, piperidylenyl,triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl. In someembodiments, -Cy- is an optionally substituted bivalent group selectedfrom cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, orcyclohexylenyl. In some embodiments, -Cy- is an optionally substitutedbivalent group selected from tetrahydrofurylenyl, azetidylenyl,pyrrolidylenyl, or piperidylenyl. In some embodiments, -Cy- is anoptionally substituted bivalent group selected from furylenyl,triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl, orthiazolylenyl. In some embodiments, -Cy- is an optionally substitutedbivalent group 2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl.

In some embodiments, L is a C₁₋₆ bivalent straight or branched saturatedor unsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —O—. In someembodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —C(R)₂—. Insome embodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —CH(R)—. Insome embodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —CH(OR)—. Insome embodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —CR(OR)—. Insome embodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —C(D)₂-. Insome embodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —C(F)₂—. Insome embodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —N(R)—. In someembodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —N(R)C(O)— or—C(O)N(R)—. In some embodiments, L is a C₁₋₆ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith —N(R)C(O)O— or —OC(O)N(R)—. In some embodiments, L is a C₁₋₆bivalent straight or branched saturated or unsaturated hydrocarbon chainwherein one to three methylene units of the chain are independently andoptionally replaced with —N(R)C(O)N(R)—. In some embodiments, L is aC₁₋₆ bivalent straight or branched saturated or unsaturated hydrocarbonchain wherein one to three methylene units of the chain areindependently and optionally replaced with —N(R)S(O)₂— or —S(O)₂N(R)—.In some embodiments, L is a C₁₋₆ bivalent straight or branched saturatedor unsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —C(O)—. In someembodiments, L is a C₁₋₆ bivalent straight or branched saturated orunsaturated hydrocarbon chain wherein one to three methylene units ofthe chain are independently and optionally replaced with —OC(O)— or—C(O)O—. In some embodiments, L is a C₁₋₆ bivalent straight or branchedsaturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith —S—. In some embodiments, L is a C₁₋₆ bivalent straight or branchedsaturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith —S(O)—. In some embodiments, L is a C₁₋₆ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith —S(O)₂—. In some embodiments, L is a C₁₋₆ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith —Si(R)₂—.

In some embodiments, L is:

In some embodiments L is:

In some embodiments, L is:

In some embodiments, L is

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is:

In some embodiments, L is

In some embodiments, L is

In some embodiments, L is selected from those depicted in Tables A-Cbelow.

As defined generally above, R¹ is hydrogen, R^(D), or an optionallysubstituted group selected from C₁₋₃ aliphatic or a 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is R^(D),or an optionally substituted group selected from C₁₋₃ aliphatic or a 4-8membered saturated or partially unsaturated monocyclic heterocyclic ringhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, orsulfur. In some embodiments, R¹ is hydrogen, R^(D), or an optionallysubstituted C₁₋₃ aliphatic group.

In some embodiments, R¹ is R^(D). In some embodiments, R¹ is —CD₃. Insome embodiments, R¹ is —CD₂CD₃.

In some embodiments, R¹ is optionally substituted C₁₋₃ aliphatic. Insome embodiments, R¹ is C₁₋₃ aliphatic optionally substituted by 1-3halogen, —OH, —OCH₃, or —C(O)N(CH₃)₂. In some embodiments, R¹ isunsubstituted C₁₋₃ aliphatic. In some embodiments, R¹ is C₁₋₃ aliphaticsubstituted by 1-3 halogen. In some embodiments, R¹ is C₁₋₃ aliphaticsubstituted by 1-3 —OH. In some embodiments, R¹ is C₁₋₃ aliphaticsubstituted by 1-3 —OCH₃. In some embodiments, R¹ is C₁₋₃ aliphaticsubstituted by 1-3 —C(O)N(CH₃)₂.

In some embodiments, R¹ is an optionally substituted 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R¹ is an optionally substituted 4 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R¹ is an optionally substituted 5 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R¹ is an optionally substituted 6 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R¹ is an optionally substituted 7 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R¹ is an optionally substituted 8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R¹ is:

In some embodiments, R¹ is selected from those depicted in Tables A-C,below.

As defined generally above, each of R² and R^(2′) is independentlyhydrogen, R^(D), or an optionally substituted group selected from C₁₋₆aliphatic, a 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring, a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or

R² and R^(2′) are optionally taken together to form ═CH₂ or ═CH—(C₁₋₃aliphatic); or

R² and R^(2′) are optionally taken together with their intervening atomsto form an optionally substituted 3-6 membered saturated or partiallyunsaturated spirocyclic ring having 0-2 heteroatoms independentlyselected from nitrogen, oxygen or sulfur.

In some embodiments, each of R² and R^(2′) is independently hydrogen,R^(D), or an optionally substituted group selected from C₁₋₆ aliphatic,a 3-8 membered saturated or partially unsaturated monocyclic carbocyclicring, a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromaticring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, R² is hydrogen. In some embodiments, R² is R^(D).In some embodiments, R² is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R² is an optionally substituted 3-8 membered saturatedor partially unsaturated monocyclic carbocyclic ring. In someembodiments, R² is an optionally substituted 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R² is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R² is C₁₋₆ aliphatic optionally substituted by 1-4halogen or —OR. In some embodiments, R² is a 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring optionally substitutedby 1-4 halogen or —OR. In some embodiments, R² is a 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur,optionally substituted by 1-4 halogen or —OR. In some embodiments, R² isa 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, optionallysubstituted by 1-4 halogen or —OR.

In some embodiments, R² is C₁₋₆ aliphatic optionally substituted by 1-3halogen, —OH, —OCH₃, or —OC(CH₃)₃. In some embodiments, R² is a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ringsubstituted by 1-3 halogen, —OH, —OCH₃, or —OC(CH₃)₃. In someembodiments, R² is a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, substituted by 1-3 halogen,—OH, —OCH₃, or —OC(CH₃)₃. In some embodiments, R² is unsubstituted C₁₋₆aliphatic.

In some embodiments, R^(2′) is hydrogen. In some embodiments, R^(2′) isR^(D). In some embodiments, R^(2′) is optionally substituted C₁₋₆aliphatic. In some embodiments, R^(2′) is an optionally substituted 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring.In some embodiments, R^(2′) is an optionally substituted 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R^(2′) is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur.

In some embodiments, R^(2′) is C₁₋₆ aliphatic optionally substituted by1-4 halogen or —OR. In some embodiments, R^(2′) is a 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ringoptionally substituted by 1-4 halogen or —OR. In some embodiments,R^(2′) is a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, optionally substituted by 1-4 halogen or—OR. In some embodiments, R^(2′) is a 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, optionally substituted by 1-4 halogen or—OR.

In some embodiments, R^(2′) is C₁₋₆ aliphatic optionally substituted by1-3 halogen, —OH, —OCH₃, or —OC(CH₃)₃. In some embodiments, R^(2′) is a3-8 membered saturated or partially unsaturated monocyclic carbocyclicring substituted by 1-3 halogen, —OH, —OCH₃, or —OC(CH₃)₃. In someembodiments, R^(2′) is a 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, substituted by 1-3 halogen,—OH, —OCH₃, or —OC(CH₃)₃. In some embodiments, R^(2′) is unsubstitutedC₁₋₆ aliphatic.

In some embodiments, each of R² and R^(2′) is independently:

In some embodiments, each of R² and R^(2′) is independently:

In some embodiments, R² is

In some embodiments, R^(2′) is

In some embodiments, R² or R^(2′) is

In some embodiments, R^(2′) is

In some embodiments, R² and R^(2′) are taken together to form ═CH₂ or═CH—(C₁₋₃ aliphatic). In some embodiments, R² and R^(2′) are takentogether to form ═CH₂. In some embodiments, R² and R^(2′) are takentogether to form ═CH—CH₃.

In some embodiments, R² and R^(2′) are taken together with theirintervening atoms to form an optionally substituted 3-6 memberedsaturated or partially unsaturated spirocyclic ring having 0-2heteroatoms independently selected from nitrogen, oxygen or sulfur. Insome embodiments, R² and R^(2′) are taken together with theirintervening atoms to form an optionally substituted 3 membered saturatedor partially unsaturated spirocyclic ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R² and R^(2′) are taken together with their interveningatoms to form an optionally substituted 4 membered saturated orpartially unsaturated spirocyclic ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R² and R^(2′) are taken together with their interveningatoms to form an optionally substituted 5 membered saturated orpartially unsaturated spirocyclic ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments, R² and R^(2′) are taken together with their interveningatoms to form an optionally substituted 6 membered saturated orpartially unsaturated spirocyclic ring having 0-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, R² and R^(2′) are taken together with theirintervening atoms to form a 3-6 membered saturated or partiallyunsaturated spirocyclic carbocyclic ring optionally substituted by 1-3halogen. In some embodiments, R² and R^(2′) are taken together withtheir intervening atoms to form spirocyclic cyclopropane optionallysubstituted by 1-3 halogen. In some embodiments, R² and R^(2′) are takentogether with their intervening atoms to form unsubstituted spirocycliccyclopropane. In some embodiments, R² and R^(2′) are taken together withtheir intervening atoms to form spirocyclic cyclobutane optionallysubstituted by 1-3 halogen. In some embodiments, R² and R^(2′) are takentogether with their intervening atoms to form unsubstituted spirocycliccyclobutane. In some embodiments, R² and R^(2′) are taken together withtheir intervening atoms to form

In some embodiments, R² and R^(2′) are taken together with theirintervening atoms to form optionally substituted spirocyclic oxetane. Insome embodiments, R² and R^(2′) are taken together with theirintervening atoms to form

In some embodiments, R² and R^(2′) are taken together with theirintervening atoms to form optionally substituted spirocyclictetrahydrofuran. In some embodiments, R² and R^(2′) are taken togetherwith their intervening atoms to form

In some embodiments, each of R² and R^(2′) is selected from thosedepicted in Tables A-C, below.

As defined generally above, R³ is hydrogen, R^(D), or an optionallysubstituted C₁₋₆ aliphatic group.

In some embodiments, R³ is hydrogen. In some embodiments, R³ is R^(D).In some embodiments, R³ is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R³ is unsubstituted C₁₋₆ aliphatic. In someembodiments, R³ is C₁₋₆ aliphatic substituted by 1-4 halogen. In someembodiments, R³ is C₁₋₆ aliphatic substituted by

or —OCH₃.

In some embodiments, R³ is:

In some embodiments, R³ is selected from those depicted in Tables A-C,below.

As defined generally above, R² and R³ are optionally taken together withtheir intervening atoms to form an optionally substituted 5-8 memberedsaturated or partially unsaturated fused ring comprising the nitrogenatom to which R³ attaches and 0-2 additional heteroatoms independentlyselected from nitrogen, oxygen or sulfur, or R², R^(2′), and R³ areoptionally taken together with their intervening atoms to form anoptionally substituted 5-8 membered saturated or partially unsaturatedfused ring comprising the nitrogen atom to which R³ attaches and 0-2additional heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, R² and R³ are taken together with their interveningatoms to form an optionally substituted 5-8 membered saturated orpartially unsaturated fused ring comprising the nitrogen atom to whichR³ attaches and 0-2 additional heteroatoms independently selected fromnitrogen, oxygen or sulfur. In some embodiments, R², R^(2′), and R³ aretaken together with their intervening atoms to form an optionallysubstituted 5-8 membered saturated or partially unsaturated fused ringcomprising the nitrogen atom to which R³ attaches and 0-2 additionalheteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, R² and R³ are taken together with their interveningatoms to form a 5-8 membered saturated or partially unsaturated fusedring substituted by 1-3 halogen, —OH, or C₁₋₆ aliphatic. In someembodiments, R², R^(2′), and R³ are taken together with theirintervening atoms to form an 5-8 membered saturated or partiallyunsaturated fused ring comprising the nitrogen atom to which R³ attachesand 0-2 additional heteroatoms independently selected from nitrogen,oxygen or sulfur.

In some embodiments, R² and R³ are taken together with their interveningatoms to form an optionally substituted fused ring:

In some embodiments, R² and R³ are taken together with their interveningatoms to form a fused ring:

each of which is optionally substituted by 1-3 halogen, —OH, or C₁₋₆aliphatic.

In some embodiments, R² and R³ are taken together with their interveningatoms to form a fused ring:

In some embodiments, R², R^(2′), and R³ are taken together with theirintervening atoms to form an optionally substituted fused ring:

In some embodiments, R², R^(2′), and R³ are taken together with theirintervening atoms to form a fused ring

which is optionally substituted by 1-3 halogen, —OH, or C₁₋₆ aliphatic.In some embodiments, R², R^(2′), and R³ are taken together with theirintervening atoms to form a fused ring

In some embodiments, R² and R³ are taken together with their interveningatoms to form an optionally substituted 5-8 membered saturated orpartially unsaturated fused ring selected from those depicted in TablesA-C, below. In some embodiments, R², R^(2′), and R³ are taken togetherwith their intervening atoms to form an optionally substituted 5-8membered saturated or partially unsaturated fused ring selected fromthose depicted in Tables A-C, below.

As defined generally above, R⁴ is hydrogen, R^(D), —CD₂OH, or anoptionally substituted C₁₋₃ aliphatic group.

In some embodiments, R⁴ is hydrogen.

In some embodiments, R⁴ is R^(D). In some embodiments, R⁴ is —CD₃.

In some embodiments, R⁴ is —CD₂OH.

In some embodiments, R⁴ is optionally substituted C₁₋₃ aliphatic. Insome embodiments, R⁴ is unsubstituted C₁₋₃ aliphatic. In someembodiments, R⁴ is methyl. In some embodiments, R⁴ is ethyl. In someembodiments, R⁴ is propyl. In some embodiments, R⁴ is C₁₋₃ aliphaticsubstituted by 1-3 halogen and OR. In some embodiments, R⁴ is C₁₋₃aliphatic substituted by 1-3 halogen or —OH. In some embodiments, R⁴ is—CH₂OH.

In some embodiments, R⁴ is selected from those depicted in Tables A-C,below.

As defined generally above, R⁵ is hydrogen, —C(O)R, —C(O)OR, —C(O)NR₂, a3-8 membered saturated or partially unsaturated monocyclic carbocyclicring, or a C₁₋₃ aliphatic group.

In some embodiments, R⁵ is hydrogen, —C(O)R, —C(O)OR, or a C₁₋₃aliphatic group.

In some embodiments, R⁵ is hydrogen.

In some embodiments, R⁵ is —C(O)R. In some embodiments, R⁵ is —C(O)R,wherein R is optionally substituted C₁₋₆ aliphatic. In some embodiments,R⁵ is —C(O)R, wherein R is C₁₋₆ aliphatic optionally substituted by 1-3—NH₂ or —NHC(O)CH₃. In some embodiments, R⁵ is

In some embodiments, R⁵ is —C(O)OR. In some embodiments, R⁵ is —C(O)OR,wherein R is optionally substituted C₁₋₆ aliphatic. In some embodiments,R⁵ is —C(O)OR, wherein R is C₁₋₆ aliphatic optionally substituted by 1-3—OC(O)CH(CH₃)₂. In some embodiments, R⁵ is

In some embodiments, R⁵ is —C(O)NR₂. In some embodiments, R⁵ is—C(O)NR₂, wherein R is independently hydrogen or an optionallysubstituted 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring. In some embodiments, R⁵ is —C(O)NR₂, wherein R isindependently hydrogen or an optionally substituted 6 membered saturatedor partially unsaturated monocyclic carbocyclic ring. In someembodiments, R⁵ is

In some embodiments, R⁵ is an optionally substituted 3-8 memberedsaturated or partially unsaturated monocyclic carbocyclic ring. In someembodiments, R⁵ is a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring optionally substituted by 1-3 halogen, —OH,or NH₂. In some embodiments, R⁵ is a 5 membered saturated or partiallyunsaturated monocyclic carbocyclic ring optionally substituted by 1-3halogen, —OH, or NH₂. In some embodiments, R⁵ is

In some embodiments, R⁵ is

In some embodiments, R⁵ is C₁₋₃ aliphatic. In some embodiments, R⁵ ismethyl.

In some embodiments, R⁵ is selected from those depicted in Tables A-C,below.

As defined generally above, each of R⁶ is independently halogen, —CN,—NO₂, —C(O)R, —C(O)OR, —C(O)NR₂, —NR₂, —NRC(O)R, —NRC(O)OR, —NRS(O)₂R,—OR, —P(O)R₂, —SR, —SF₅, —S(O)R, —S(O)₂R, —S(O)(NH)R, —C(═NR)—OR,—O—C(═NR)—R, or R; or two R⁶ groups are optionally taken together toform ═O.

In some embodiments, R⁶ is halogen. In some embodiments, R⁶ is —CN. Insome embodiments, R⁶ is —NO₂. In some embodiments, R⁶ is —C(O)R. In someembodiments, R⁶ is —C(O)OR. In some embodiments, R⁶ is —C(O)NR₂. In someembodiments, R⁶ is —NR₂. In some embodiments, R⁶ is —NRC(O)R. In someembodiments, R⁶ is —NRC(O)OR. In some embodiments, R⁶ is —NRS(O)₂R. Insome embodiments, R⁶ is —OR. In some embodiments, R⁶ is —P(O)R₂. In someembodiments, R⁶ is —SR. In some embodiments, R⁶ is —SF₅. In someembodiments, R⁶ is —S(CF₃)s. In some embodiments, R⁶ is —S(O)R. In someembodiments, R⁶ is —S(O)₂R. In some embodiments, R⁶ is —S(O)(NH)R. Insome embodiments, R⁶ is —C(═NR)—OR. In some embodiments, R⁶ is—O—C(═NR)—R. In some embodiments, R⁶ is R. In some embodiments, two R⁶groups are taken together to form ═O.

In some embodiments, R⁶ is F. In some embodiments, R⁶ is Cl. In someembodiments, R⁶ is I.

In some embodiments, R⁶ is optionally substituted C₁₋₆ aliphatic. Insome embodiments, R⁶ is unsubstituted C₁₋₆ aliphatic. In someembodiments, R⁶ is C₁₋₆ aliphatic substituted by 1-5 halogen, —CN, or—OR. In some embodiments, R⁶ is C₁₋₆ aliphatic substituted by 1-5halogen, —CN, or —OH. In some embodiments, R⁶ is C₁₋₆ aliphaticsubstituted by 1-5 halogen or —OH.

In some embodiments, R⁶ is —C(O)R, wherein R is optionally substitutedC₁₋₆ aliphatic. In some embodiments, R⁶ is —C(O)R, wherein R isunsubstituted C₁₋₆ aliphatic. In some embodiments, R⁶ is —C(O)R, whereinR is C₁₋₆ aliphatic substituted by 1-4 halogen or —O—(C₁₋₆ aliphaticoptionally substituted by 1-3 halogen). In some embodiments, R⁶ is—C(O)R, wherein R is C₁₋₆ aliphatic substituted by —O—(C₁₋₆ aliphaticoptionally substituted by 1-3 halogen). In some embodiments, R⁶ is—C(O)R, wherein R is C₁₋₆ aliphatic substituted by —OCH₂CF₃. In someembodiments, R⁶ is —C(O)—CH₂OCH₂CF₃ or —C(O)—CH₂CH₂OCH₂CF₃.

In some embodiments, R⁶ is —NR₂, wherein each R is independentlyHydrogen or optionally substituted C₁₋₆ aliphatic. In some embodiments,R⁶ is —NR₂, wherein R is independently Hydrogen or unsubstituted C₁₋₆aliphatic. In some embodiments, R⁶ is —NR₂, wherein R is independentlyHydrogen or C₁₋₆ aliphatic substituted by 1-4 halogen. In someembodiments, R⁶ is —NR₂, wherein R is independently C₁₋₆ aliphaticsubstituted by optionally substituted phenyl or a 4-8 membered saturatedor partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur. Insome embodiments, R⁶ is —NR₂, wherein R is independently C₁₋₆ aliphaticsubstituted by phenyl or a 4-6 membered saturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, wherein the phenyl and heterocyclic ring isoptionally and independently substituted by 1-3 halogen. In someembodiments, R⁶ is

In some embodiments, R⁶ is —OR, wherein R is Hydrogen or optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R⁶ is —OR, wherein R isHydrogen or unsubstituted C₁₋₆ aliphatic. In some embodiments, R⁶ is—OR, wherein R is Hydrogen or C₁₋₆ aliphatic substituted by 1-4 halogen.

In some embodiments, R⁶ is —C(═NR)—OR, wherein each R is independentlyHydrogen or optionally substituted C₁₋₆ aliphatic. In some embodiments,R⁶ is —C(═NR)—OR, wherein R is independently Hydrogen or unsubstitutedC₁₋₆ aliphatic. In some embodiments, R⁶ is —C(═NH)—OR, wherein R isoptionally substituted C₁₋₆ aliphatic. In some embodiments, R⁶ is—C(═NH)—OR, wherein R is unsubstituted C₁₋₆ aliphatic. In someembodiments, R⁶ is —C(═NH)—OC(CH₃)₃.

In some embodiments, R⁶ is:

In some embodiments, two R⁶ are attached to the same position on Ring A.

In some embodiments, R⁶ is selected from those depicted in Tables A-C,below.

As defined generally above, each R is independently hydrogen or anoptionally substituted group selected from C₁₋₆ aliphatic, a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,phenyl, a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromaticring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or two R groups on the same nitrogen are optionallytaken together with their intervening atoms to form a 4-7 memberedsaturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups.

In some embodiments, R is hydrogen. In some embodiments, R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R is an optionallysubstituted 3-8 membered saturated or partially unsaturated monocycliccarbocyclic ring. In some embodiments, R is optionally substitutedphenyl. In some embodiments, R is an optionally substituted 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.In some embodiments, R is an optionally substituted 5-6 memberedmonocyclic heteroaromatic ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur. In some embodiments, two Rgroups on the same nitrogen are taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen and sulfur, optionallysubstituted with 1-2 oxo groups.

In some embodiments, R is C₁₋₆ aliphatic optionally substituted by 1-4halogen, —CN, —NO₂, —OH, —NH₂, —OCH₃, or —C(O)N(CH₃)₂. In someembodiments, R is unsubstituted C₁₋₆ aliphatic.

In some embodiments, each R is selected from those depicted in TablesA-C, below.

As defined generally above, R^(D) is a C₁₋₄ aliphatic group wherein oneor more hydrogens are replaced by deuterium.

In some embodiments, R^(D) is a C₁₋₃ aliphatic group wherein one or morehydrogens are replaced by deuterium. In some embodiments, R^(D) is aC₁₋₂ aliphatic group wherein one or more hydrogens are replaced bydeuteriumn. In some embodiments, R^(D) is a methyl group wherein one ormore hydrogens are replaced by deuteriumn. In some embodiments, R^(D) is—CD₃. In some embodiments, R^(D) is —CD₂CD₃.

In some embodiments, R^(D) is selected from those depicted in TablesA-C, below.

As defined generally above, X is N or CH.

In some embodiments, X is N. In some embodiments, X is CH.

In some embodiments, X is selected from those depicted in Tables A-C,below.

As defined generally above, n is 0, 1, 2, 3, 4 or 5.

In some embodiments, n is 0. In some embodiments, n is 1, 2, 3, 4 or 5.In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2,or 3. In some embodiments, n is 1. In some embodiments, n is 2. In someembodiments, n is 3. In some embodiments, n is 4. In some embodiments, nis 5.

In some embodiments, n is selected from those depicted in Tables A-C,below.

In some embodiments, the present invention provides a compound ofFormula I′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R¹, R², R³, R⁴, R⁶, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula II:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R¹, R², R^(2′), R³, R⁴, R⁶, and n is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula II′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R¹, R², R³, R⁴, R⁶, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula III:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R¹, R², R³, R⁴, R⁶, and n n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula III′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R¹, R², R³, R⁶, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula IV:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R², R^(2′), R³, R⁶, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula IV′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R², R³, R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula V:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R², R^(2′), R⁶, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula V′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R², R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula VI-a, VI-b, VI-c, or VI-d:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,R², R^(2′), R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula VI′-a, VI′-b, VI′-c, or VI′-d:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,R², R⁶, and n is as defined above and described in embodiments herein,both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula VII:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R², R^(2′), R⁴, R⁶, and n is as defined above and described inembodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula VII′:

or a pharmaceutically acceptable salt thereof, wherein each of Ring A,L, R², R⁴, R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound ofFormula VI′-a, VI′-b, VI′-c, or VI′-d, or a pharmaceutically acceptablesalt thereof, wherein

R² is unsubstituted C₁₋₆ aliphatic, or R^(D);

wherein one of R⁶ is —CF₃; n′ is 1, 2, 3, or 4; and n″ is 1, 2, or 3;or

wherein n′″ is 0, 1, 2, or 3; and

each of R⁶ and R^(D) is as defined above and described in embodimentsherein.

In some embodiments,

wherein one of R⁶ is —CF₃; each of the other R^(6′) is as defined aboveand described in embodiments herein; and n′ is 1, 2, 3, or 4.

In some embodiments,

wherein one of R⁶ is —CF₃; each of the other R⁶ is as defined above anddescribed in embodiments herein; and n″ is 1, 2, or 3.

In some embodiments

wherein each R⁶ is as defined above and described in embodiments herein;and n′″ is 0, 1, 2, or 3.

In some embodiments, n′ is 1. In some embodiments, n′ is 2. In someembodiments, n′ is 3. In some embodiments, n′ is 4. In some embodiments,n″ is 1. In some embodiments, n″ is 2. In some embodiments, n″ is 3. Insome embodiments, n′″ is 0. In some embodiments, n′″ is 1. In someembodiments, n′″ is 2. In some embodiments, n′″ is 3.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, the present invention provides a compound ofFormula VIII′-a, VIII′-b or VIII′-c:

or a pharmaceutically acceptable salt thereof, wherein

R² is unsubstituted C₁₋₆ aliphatic, or R^(D);

n is 0, 1, 2, 3, or 4 in formulas VIII′-a and VIII′-b, and 0, 1, 2, or 3in formula VIII′-c; and

each of R⁶ and R^(D) is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula I wherein said compound is other than a compound selected from:

Exemplary compounds of the invention are set forth in Tables A-C, below.

TABLE A Exemplary Compounds

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I -85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I -124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-319

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-337

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-369

I-370

I-371

I-372

I-373

I-374

I-375

I-376

I-377

I-381

I-382

I-383

I-384

I-385

I-386

I-387

I-388

I-389

I-390

I-394

I-395

I-396

I-397

I-398

I-400

I-401

I-402

I-403

I-404

I-405

I-406

I-407

I-408

I-409

TABLE B Exemplary Compounds

I-410

I-412

I-413

I-413

I-414

I-415

I-416

I-417

I-418

I-419

I-420

I-421

I-422

I-423

I-424

I-425

I-426

I-427

I-428

I-429

I-430

I-431

I-432

I-433

I-434

I-435

I-436

I-437

I-438

I-439

I-440

I-441

I-442

I-443

I-444

I-445

I-446

I-447

I-448

I-449

I-450

I_451

I-452

I-453

I-454

I-455

I-456

I-457

I-458

I-459

I-460

I-461

I-462

I-463

I-464

I-465

I-466

I-467

I-468

I-469

I-470

I-471

I-472

I-473

I-474

I-475

I-476

I-477

I-478

I-479

I-480

I-481

I-482

I-483

I-484

I-485

I-486

I-487

I-488

I-489

I-490

I-491

I-492

I-493

I-494

I-495

I-496

I-497

I-498

I-499

I-500

I-501

I-502

I-503

I-504

I-505

I-506

I-507

I-508

I-509

I-510

I-511

I-512

I-513

I-514

I-515

I-516

I-517

I-518

I-519

I-520

I-521

I-522

I-523

I-524

I-525

I-526

I-527

I-528

I-529

I-530

I-531

I-532

I-533

I-534

I-535

I-536

I-537

I-538

I-539

I-540

I-541

I-542

I-543

I-544

I-545

I-546

I-547

I-548

I-549

I-550

I-551

I-552

I-553

I-554

I-555

I-556

I-557

I-558

I-559

I-560

I-561

I-562

I-563

I-564

I-565

I-566

I-567

I-568

I-569

I-570

I-571

I-572

I-573

I-574

I-575

I-576

I-577

I-578

I-579

I-580

I-581

I-582

I-583

I-584

I-585

I-586

I-587

I-588

I-589

I-590

I-591

I-592

I-593

I-594

I-595

I-596

I-597

I-598

I-599

I-600

I-601

I-602

I-603

I-604

I-605

I-606

I-607

I-608

I-609

I-610

I-611

I-612

I-613

I-614

I-615

I-616

I-617

I-618

I-619

I-620

I-621

I-622

I-623

I-624

I-625

I-626

I-627

I-628

I-629

I-630

I-631

I-632

I-633

I-634

I-635

I-636

I-637

I-638

I-639

I-640

I-641

I-642

I-643

I-644

I-645

I-646

I-647

I-648

I-649

I-650

I-651

I-652

I-653

I-655

I-656

I-657

I-658

I-659

I-660

I-661

I-662

I-663

I-664

I-665

I-666

I-667

I-668

I-669

I-670

I-671

I-672

I-673

I-674

I-675

I-676

I-677

I-678

I-679

I-680

I-681

I-682

I-683

I-684

I-685

I-686

I-687

I-688

I-689

I-690

I-691

I-692

I-693

I-694

I-695

I-696

I-697

I-698

I-699

I-703

I-704

I-705

I-706

I-707

I-708

I-709

I-710

I-711

I-712

I-713

I-714

I-715

I-716

I-717

I-718

I-719

I-720

I-721

I-722

I-723

I-724

I-725

I-726

I-727

I-728

I-729

I-730

I-731

I-732

I-733

I-734

I-735

I-736

i-737

I-738

I-739

I-740

I-741

I-742

I-743

I-744

I-745

I-746

I-747

I-748

I-749

I-750

I-751

I-752

I-753

I-754

I-755

I-756

I-757

I-758

I-759

I-760

I-761

I-762

I-763

I-764

I-765

I-766

I-767

TABLE C Exemplary Compounds

I-768

I-769

I-770

I-771

I-772

I-773

I-774

I-775

I-776

I-777

I-778

I-779

I-780

I-781

I-782

I-783

I-784

I-785

I-786

I-787

I-788

I-789

I-790

I-791

I-792

I-793

I-794

I-795

I-796

I-797

I-798

I-799

I-800

I-801

I-802

I-803

I-804

I-805

I-806

I-807

I-808

I-809

I-810

I-811

I-812

I-813

I-814

I-815

I-816

I-817

I-818

I-819

I-820

I-821

I-822

I-823

I-824

I-825

I-826

I-827

I-828

I-829

I-830

I-831

I-832

I-833

I-834

I-835

I-836

I-837

I-838

I-839

I-840

I-841

I-842

I-843

I-844

I-845

I-846

I-847

I-848

I-849

I-850

I-851

I-852

I-853

I-854

I-855

I-856

I-857

I-858

I-859

I-860

I-861

I-862

I-863

I-864

I-865

I-866

I-867

I-868

I-869

I-870

I-871

I-872

I-873

I-874

I-875

I-876

I-877

I-878

I-879

I-880

I-881

I-882

I-883

I-884

I-885

I-886

I-887

I-888

I-889

I-890

I-891

I-892

I-893

I-894

I-895

I-896

I-897

I-898

I-899

I-900

I-901

I-902

I-903

I-904

I-905

I-906

I-907

I-908

I-909

I-910

I-911

I-912

I-913

I-914

I-915

I-916

I-917

I-918

I-919

I-920

I-921

I-922

I-923

I-924

I-925

I-926

I-927

I-928

I-929

I-930

I-931

I-932

I-933

I-934

I-935

I-936

I-937

I-938

I-939

I-940

I-941

I-942

I-943

I-944

I-945

I-946

I-947

I-948

I-949

I-950

I-951

I-952

I-953

I-954

I-955

I-956

I-957

I-958

I-959

I-960

I-961

I-962

I-963

I-964

I-965

I-966

I-967

I-968

I-969

I-970

I-971

I-972

I-973

I-974

I-975

I-976

I-977

I-978

I-979

I-980

I-981

I-982

I-983

I-984

I-985

I-986

I-987

I-988

I-989

I-990

I-991

I-992

I-993

I-994

I-995

I-996

I-997

I-998

I-999

I-1000

I-1001

I-1002

I-1003

I-1004

I-1005

I-1006

I-1007

I-1008

I-1009

I-1010

I-1011

I-1012

I-1013

I-1014

I-1015

I-1016

I-1017

I-1018

I-1019

I-1020

I-1021

I-1022

I-1023

I-1024

I-1025

I-1026

I-1027

I-1028

I-1029

I-1030

I-1031

I-1032

I-1033

I-1034

I-1035

I-1036

I-1037

I-1038

I-1039

I-1040

I-1041

I-1042

I-1043

I-1044

I-1045

I-1046

I-1047

I-1048

I-1049

I-1050

I-1051

I-1052

I-1053

I-1054

I-1055

I-1056

I-1057

I-1058

I-1059

I-1060

I-1061

I-1062

I-1063

I-1064

I-1065

I-1066

I-1067

I-1068

I-1069

I-1070

I-1071

I-1072

I-1073

I-1074

I-1075

I-1076

I-1077

I-1078

I-1079

I-1080

I-1081

I-1082

I-1083

I-1084

I-1085

I-1086

I-1087

I-1088

I-1089

I-1090

I-1091

I-1092

I-1093

I-1094

I-1095

I-1096

I-1097

I-1098

I-1099

I-1100

I-1101

I-1102

I-1103

I-1104

I-1105

I-1106

I-1107

I-1108

I-1109

I-1110

I-1111

I-1112

I-1113

I-1114

I-1115

I-1116

I-1117

I-1118

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4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group (“PG”),leaving group (“LG”), or transformation condition is depicted, one ofordinary skill in the art will appreciate that other protecting groups,leaving groups, and transformation conditions are also suitable and arecontemplated. Such groups and transformations are described in detail inMarch's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, M. B. Smith and J. March, 5^(th) Edition, John Wiley & Sons,2001, Comprehensive Organic Transformations, R. C. Larock, 2^(nd)Edition, John Wiley & Sons, 1999, and Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, the entirety of each of which is hereby incorporated hereinby reference.

As used herein, the phrase “leaving group” (LG) includes, but is notlimited to, halogens (e.g. fluoride, chloride, bromide, iodide),sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate,nosylate, triflate), diazonium, and the like.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, andPhilip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart,New York, 1994, the entireties of which is incorporated herein byreference. Examples of suitable hydroxyl protecting groups include, butare not limited to, esters, allyl ethers, ethers, silyl ethers, alkylethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of suchesters include formates, acetates, carbonates, and sulfonates. Specificexamples include formate, benzoyl formate, chloroacetate,trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate,4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate,4-methoxy-crotonate, benzoate, p-benzylbenzoate,2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl,ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, andPhilip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart,New York, 1994, the entireties of which is incorporated herein byreference. Suitable amino protecting groups include, but are not limitedto, aralkylamines, carbamates, cyclic imides, allyl amines, amides, andthe like. Examples of such groups include t-butyloxycarbonyl (BOC),ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl,allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide,benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl,chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl,trifluoroacetyl, benzoyl, and the like.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. See, for example,“March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. andMarch, J., John Wiley & Sons, New York: 2001, the entirety of which isincorporated herein by reference. Such interconversions may require oneor more of the aforementioned techniques, and certain methods forsynthesizing compounds of the invention are described below.

In one aspect, the present invention provides a method for synthesizinga compound of Formula I, or subformulae thereof, or a salt thereof,comprising reacting a compound of formula:

or a salt thereof, and a compound of formula:

or a salt thereof, wherein LG is a leaving group, and each of Ring A, L,R¹, R², R^(2′), R³, R⁴, R⁵, R⁶, and n is as defined above and describedin embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula:

or a salt thereof, wherein each of Ring A, L, R⁵, R⁶, and n is asdefined above and described in embodiments herein, both singly and incombination.

In some embodiments, the present invention provides a compound offormula:

or a salt thereof, wherein LG is a leaving group, and each of R¹, R²,R^(2′), R³, and R⁴ is as defined above and described in embodimentsherein, both singly and in combination

In some embodiments, the present invention provides a method forsynthesizing a compound of Formula VI-a, or a salt thereof, comprisingreacting a compound of formula:

or a salt thereof, and a compound of formula:

salt thereof, wherein LG is a leaving group, and each of Ring A, R²,R^(2′), R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a method forsynthesizing a compound of Formula VI-b, or a salt thereof, comprisingreacting a compound of formula:

or a salt thereof, and a compound of formula:

or a salt thereof, wherein LG is a leaving group, and each of Ring A,R², R^(2′), R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a method forsynthesizing a compound of Formula VI-c, or a salt thereof, comprisingreacting a compound of formula:

or a salt thereof, and a compound of formula

or a salt thereof, wherein LG is a leaving group, and each of Ring A,R², R^(2′), R⁶, and n is as defined above and described in embodimentsherein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula:

or a salt thereof, wherein each of Ring A, R⁶, and n is as defined aboveand described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula:

or a salt thereof, wherein each of Ring A, R⁶, and n is as defined aboveand described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula:

or a salt thereof, wherein each of Ring A, R⁶, and n is as defined aboveand described in embodiments herein, both singly and in combination.

In some embodiments, the present invention provides a compound offormula:

or a salt thereof, wherein LG is a leaving group, and each of R² andR^(2′) is as defined above and described in embodiments herein, bothsingly and in combination.

5. Uses, Formulation and Administration

The present invention provides methods of treating a subject withcancer. The methods comprise administering a pharmaceutically effectiveamount of a chemical entity of the invention described herein (e.g., achemical entity that is a compound of the invention described herein, ora pharmaceutically acceptable salt thereof, or a composition thereof) tothe subject.

The present invention also provides methods of inhibiting cancer cellgrowth, including processes of cellular proliferation, invasiveness, andmetastasis in a biological system. In some embodiments, the methods areemployed to inhibit or reduce cancer cell growth, invasiveness,metastasis, or tumor incidence in a subject with cancer.

The present invention also provides use of a chemical entity of theinvention described herein for treating a subject with cancer and use ofsuch compounds in the manufacture of an medicament for treating asubject with cancer.

The present invention also provides methods of treating a subject withcancer, comprising administering a wolframin-dependent modulator ofendoplasmic reticulum (ER) stress and/or unfold protein response (UPR)or a wolframin-dependent modulator of calcium flux at or in the ER tothe subject. In some embodiments, a method of treating a subject withcancer, comprises administering a wolframin-dependent modulator ofendoplasmic reticulum (ER) stress and/or unfold protein response (UPR)to the subject.

In some embodiments, the present invention provides an in vitro methodcomprising administering a wolframin modulator in a cancer cell or tumorof a subject with cancer.

The present invention also provides methods of treating a subject withcancer, comprising:

measuring an expression level of wolfram syndrome 1 gene (WFS1) or theprotein encoded by WFS1 in a cancer cell or tumor of the subject; and

administering a wolframin-dependent modulator of endoplasmic reticulum(ER) stress and/or unfold protein response (UPR) or awolframin-dependent modulator of calcium flux at or in the ER to thesubject if said expression level of WFS1 or the protein encoded by WFS1is greater than a reference value from a subject with the same cancer.

The present invention also provides a method of sensitizing a cancercell or tumor of a subject with cancer to an anticancer treatment,comprising increasing the expression of wolframin in a cancer cell ortumor of a subject with cancer; and wherein the anticancer treatmentcomprises administering a chemical entity of the invention describedherein to the cancer cell or tumor.

The present invention also provides a method of treating a subject withcancer comprising increasing the expression of wolframin in a cancercell or tumor of a subject with cancer, and administering a chemicalentity of the invention described herein to the subject.

The present invention also provides a method of treating a subject withcancer, comprising measuring an expression level of wolfram syndrome 1gene (WFS1) or the protein encoded by WFS1 in a cancer cell or tumor ofthe subject, and administering a wolframin-dependent modulator ofendoplasmic reticulum (ER) stress and/or unfolded protein response (UPR)or a wolframin-dependent modulator of calcium flux at or in the ER tothe subject if said expression level of WFS1 or the protein encoded byWFS1 is greater than a reference value from a subject with the samecancer.

The present invention also provides a method of measuring a bindingconstant of a candidate molecule to a wolframin complex, comprisingmeasuring the displacement of a radiolabeled probe that binds to awolframin complex by a candidate molecule which may bind to thewolframin complex, wherein the radiolabeled probe is a radiolabeledwolframin-dependent modulator, such as a or a radiolabeledwolframin-dependent modulator of calcium flux at or in the ER orradiolabeled wolframin-dependent modulator of endoplasmic reticulum (ER)stress and/or unfolded protein response (UPR). In some embodiments, awolframin complex is a complex of wolframin and wolframin-binding orwolframin-associated protein(s).

The present invention also provides a method of measuring a bindingconstant of a candidate molecule to wolframin, comprising measuring thedisplacement of a radiolabeled probe that binds to wolframin by acandidate molecule which may bind to the wolframin, wherein theradiolabeled probe is a radiolabeled wolframin-dependent modulator, suchas a or a radiolabeled wolframin-dependent modulator of calcium flux ator in the ER or radiolabeled wolframin-dependent modulator ofendoplasmic reticulum (ER) stress and/or unfolded protein response(UPR).

The present invention also provides a method of screening candidatemolecules to determine whether they are wolframin-dependent modulator ofendoplasmic reticulum (ER) stress and/or unfolded protein response(UPR), comprising introducing a candidate molecule into a cancer cell(s)that comprises a wolframin complex and has been treated with anothermolecule which binds to the wolframin complex and modulates ER and/orUPR or its binding to the wolframin complex modulates ER and/or UPR.

The present invention also provides a method of screening candidatemolecules to determine whether they are wolframin-dependent modulator ofcalcium flux at or in the endoplasmic reticulum (ER), comprisingintroducing a candidate molecule into a cancer cell(s) that comprises awolframin complex and has been treated with another molecule which bindsto the wolframin complex and modulates calcium flux at or in the ER orits binding to the wolframin complex modulates calcium flux at or in theER.

The present invention also provides a method of screening candidatemolecules to determine whether they are wolframin-dependent modulator(e.g., wolframin-dependent modulator of endoplasmic reticulum (ER)stress and/or unfolded protein response (UPR) or a wolframin-dependentmodulator calcium flux at or in the endoplasmic reticulum (ER)), saidmethod comprising monitoring a sensitive cell for induction of calciumflux, ER Stress, or the UPR; and comparing the degree to which the sameeffect occurs in a genetically matched cell that has been engineered tonot express wolframin or to express a different level of wolframin, orwhich through a spontaneous mutation is similar in all regards to thesensitive cell except for the level of wolframin that is expressed.

The present invention also provides a method of sensitizing a cancercell or tumor of a subject with cancer to an anticancer treatment,comprising increasing the expression of wolframin in a cancer cell ortumor of a subject with cancer; and wherein the anticancer treatmentcomprises administering a chemical entity described herein to the cancercell or tumor.

The present invention also provides a method of sensitizing a cancercell or tumor of a subject to an anticancer treatment, comprising:increasing the expression of wolframin in a cancer cell or tumor of asubject with cancer; and wherein the anticancer treatment comprisesadministering a wolframin-dependent modulator, such as awolframin-dependent modulator of endoplasmic reticulum (ER) stressand/or unfolded protein response (UPR) or a wolframin-dependentmodulator of calcium flux at or in the ER, to the cancer cell or tumor.

The present invention also provides a method of treating a subject withcancer, comprising: increasing the expression of wolframin in a cancercell or tumor of a subject with cancer; and administering a chemicalentity of the invention described herein to the subject.

The present invention also provides a method of treating a subject withcancer, comprising: increasing the expression of wolframin in a cancercell or tumor of a subject with cancer; and administering awolframin-dependent modulator described herein, such as awolframin-dependent modulator of endoplasmic reticulum (ER) stressand/or unfolded protein response (UPR) or a wolframin-dependentmodulator of calcium flux at or in the ER, to the subject.

In some embodiments, a method of treating a subject with cancercomprises increasing the expression of wolframin in a cancer cell ortumor of a subject with cancer; and administering a chemical entity ofthe invention as described herein to the subject.

In some embodiments, a method of treating a subject with cancercomprises increasing the expression of wolframin in a cancer cell ortumor of a subject with cancer; and administering a wolframin-dependentmodulator of endoplasmic reticulum (ER) stress and/or unfold proteinresponse (UPR) or a wolframin-dependent modulator of calcium flux(collectively, a “wolframin-dependent modulator”) to the subject. Inembodiments, such a wolframin-dependent modulator (e.g., awolframin-dependent modulator of endoplasmic reticulum (ER) stressand/or unfold protein response (UPR) or a wolframin-dependent modulatorof calcium flux) is a small molecule (e.g., a chemical entity of theinvention described herein), a polypeptide, a nucleic acid molecule, oran antibody or fragment thereof.

In some embodiments, a method of treating a subject with cancercomprises measuring an expression level of wolfram syndrome 1 gene(WFS1) or the protein encoded by WFS1 (wolframin) in a cancer cell ortumor of a subject with cancer; and administering a wolframin-dependentmodulator (e.g, wolframin-dependent modulator of endoplasmic reticulum(ER) stress and/or unfold protein response (UPR) or wolframin-dependentmodulator of calcium flux) to the subject if said expression level ofWFS1 or the protein encoded by WFS1 is greater than a reference valuefrom a subject with the same cancer. In some embodiments, awolframin-dependent modulator (e.g, wolframin-dependent endoplasmicreticulum (ER) stress and/or unfold protein response (UPR) orwolframin-dependent modulator of calcium flux) is a small molecule(e.g., a chemical entity of the invention described herein), apolypeptide, a nucleic acid molecule, or an antibody or fragmentthereof.

In some embodiments, a method of sensitizing a cancer cell or tumor of asubject with cancer to an anticancer treatment comprises increasing theexpression of wolframin in a cancer cell or tumor of the subject; andwherein the anticancer treatment comprises administering any of thewolframin-modulators of the invention (e.g., a wolframin-dependentmodulator of endoplasmic reticulum (ER) stress and/or unfolded proteinresponse (UPR) or a wolframin-dependent modulator of calcium flux) tothe cancer cell or tumor. In some embodiments, the wolframin-modulatorsare small molecules (e.g, a chemical entity of the invention asdescribed herein. In some embodiments, the wolframin-modulators arepolypeptides, nucleic acid molecules, or antibodies or fragmentsthereof.

In some embodiments, a chemical entity of the invention described hereinis a compound of the invention as described herein. In some embodiments,a chemical entity of the invention described herein is apharmaceutically acceptable salt of a compound of the invention asdescribed herein. In some embodiments, a chemical entity of theinvention described herein is a composition of the invention asdescribed herein.

Also provided herein is a kit for predicting the likelihood of responseof a subject with cancer to an anticancer treatment: a) reagents tomeasure an expression level of wolfram syndrome 1 gene (WFS1) or theprotein encoded by WFS1 in a cancer cell or tumor of the subject; and b)a guideline comprising instructions about whether or not a patient withcancer to be under an anticancer treatment would respond to ananticancer treatment with a chemical entity of the invention describedherein, wherein an expression level of WFS1 or the protein encoded byWFS1 greater than a reference value from a subject with the same cancerindicates that the subject to be under an anticancer treatment is likelyto respond to the anticancer treatment with a chemical entity of theinvention described herein.

In some embodiments of the kits and methods provided herein, awolframin-dependent moleculator is a wolframin-dependent modulator ofendoplasmic reticulum (ER) stress and/or unfolded protein response (UPR)or a wolframin-dependent modulator of calcium flux at or in the ER. Insome embodiments, each of the wolframin-dependent moleculators is asmall molecule. In embodiments, said small molecule is a chemical entityof the invention described herein . . . .

In some embodiments of the kits and methods provided herein, awolframin-dependent moleculator is a wolframin-dependent moleculator ofendoplasmic reticulum (ER) stress and/or unfolded protein response (UPR)or a wolframin-dependent modulator of calcium flux at or in the ER. Insome embodiments, each of the wolframin-dependent moleculators is apolypeptide, nucleic acid molecule, or an antibody or a fragmentthereof.

In some embodiments, a wolframin-dependent modulator is a polypeptide.

In some embodiments, a wolframin-dependent modulator is a nucleic acidmolecule. In some embodiments, a nucleic acid molecule modulatesactivity or function of a wolframin complex to cause ER stress and/orUPR. In some embodiments, this can be monitored using conventionalmethods well known in the art, for example by screening using real timePCR as described in the examples.

In embodiments, a wolframin-dependent modulator is an antibody orfragment thereof (e.g., an antibody that can open a wolframin Ca²⁺channel, or a fragment thereof).

The present invention also provides a method of predicting thelikelihood of response of a subject with cancer to an anticancertreatment with a compound or composition of the invention describedherein. In one embodiment, the method comprises measuring a level ofendoplasmic reticulum (ER) stress or unfold protein response (UPR) in atumor of the subject.

The present invention also provides a method of treating a subject withcancer, comprising: a) measuring an expression level of wolfram syndrome1 gene (WFS1) or the protein encoded by WFS1 in a cancer cell or tumorof a subject with cancer; and b) administering a pharmaceuticallyeffective amount of a chemical entity of the invention described hereinto the subject if said expression level of WFS1 or the protein encodedby WFS1 is greater than a reference value from a subject with the samecancer.

In some embodiments, the present invention provides a method of treatinga subject with cancer, comprising administering a pharmaceuticallyeffective amount of a chemical entity of the invention described herein,wherein an expression level of wolfram syndrome 1 gene (WFS1) or theprotein encoded by WFS1 in a tumor of the subject is greater than areference value from a subject with the same cancer.

In some embodiments, the present invention provides an in vitro methodfor predicting the likelihood of response of a subject with cancer to ananticancer treatment with a chemical entity of the invention describedherein, comprising measuring an expression level of endoplasmicreticulum (ER) stress or unfold protein (UPR) response in a tumor sampleobtained from the subject.

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention, or a pharmaceuticallyacceptable derivative thereof, and a pharmaceutically acceptablecarrier, adjuvant, or vehicle. In certain embodiments, the amount ofcompound in compositions of this invention is such that is effective tocause cancer cell death in a biological sample or in a patient. Incertain embodiments, the amount of compound in compositions of thisinvention is such that is effective to induce UPR in cancer cells in abiological sample or in a patient. In certain embodiments, the amount ofcompound in compositions of this invention is such that is effective toinduce ER stress in cancer cells in a biological sample or in a patient.In certain embodiments, the amount of compound in compositions of thisinvention is such that is effective to induce calcium release from theER via WFS1 in cancer cells in a biological sample or in a patient. Incertain embodiments, a composition of this invention is formulated foradministration to a patient in need of such composition. In someembodiments, a composition of this invention is formulated for oraladministration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an active metabolite or residue thereof.

As used herein, the term “active metabolite or residue thereof” meansthat a metabolite or residue thereof also results in cell death.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. Fatty acids, such as oleic acid andits glyceride derivatives are useful in the preparation of injectables,as are natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of theinhibitor can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful fortreatment of cellular proliferative disorders. As provided above, thecompounds described herein have been found capable of causing calciumrelease from the endoplasmic reticulum (ER) via a putative Ca²⁺ channelknown as Wolframin (WFS1), inducing ER stress and the “unfolded proteinresponse” (UPR), and resulting cell death.

In some embodiments, the present invention provides a method fortreating a cellular proliferative disorder in a patient comprisingadministering to said patient a compound of the present invention, or acomposition comprising said compound. In some embodiments, the presentinvention provides a compound of the present invention, or a compositioncomprising said compound, for use in the treatment of a cellularproliferative disorder. Such disorders are described in detail herein.In some embodiments, a cellular proliferative disorder is a cancercharacterized by Wolframin (WFS1) overexpression in the cancer cells. Insome embodiments, a cancer characterized by Wolframin (WFS1)overexpression is selected from non-small cell lung cancer (NSCLC),myeloma, multiple myeloma, hepatocellular carcinoma (HCC), breastcancer, bladder cancer, kidney cancer, and melanoma. In someembodiments, a method for treating a cellular proliferative disorder asdescribed herein further comprises determining the Wolframin (WFS1)expression level. In some embodiments, the Wolframin (WFS1) expressionlevel is determined by immunohistochemistry and/or microarray probeintensity.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

In some embodiments, the present invention provides a method forinducing ER stress in a patient in need thereof, comprisingadministering a compound of the present invention, or a compositioncomprising said compound. In some embodiments, the present inventionprovides a method for inducing the “unfolded protein response” (UPR) ina patient in need thereof, comprising administering a compound of thepresent invention, or a composition comprising said compound. In someembodiments, the present invention provides a method for causing calciumrelease from the endoplasmic reticulum (ER) via a putative Ca²⁺ channelknown as Wolframin (WFS1) in a patient in need thereof, comprisingadministering a compound of the present invention, or a compositioncomprising said compound.

In some embodiments, the present invention provides a compound of anyone of Formulas I-VIII, or a composition comprising said compound, foruse in causing calcium release from the endoplasmic reticulum (ER) via aputative Ca²⁺ channel known as Wolframin (WFS1) in a subject in needthereof. In some embodiments, the present invention provides a compoundof any one of Formulas I-VIII, or a composition comprising saidcompound, for use in inducing ER stress in a subject in need thereof. Insome embodiments, the present invention provides a compound of any oneof Formulas I-VIII, or a composition comprising said compound, for usein inducing the “unfolded protein response” (UPR) in a subject in needthereof.

The activity of a compound utilized in this invention as an inhibitor ofcell proliferation may be assayed in vitro or in vivo. Detailedconditions for assaying a compound in this invention are set forth inthe Examples below.

Cellular Proliferative Disorders

The present invention features methods and compositions for thediagnosis and prognosis of cellular proliferative disorders (e.g.,cancer) and the treatment of these disorders. Cellular proliferativedisorders described herein include, e.g., cancer, obesity, andproliferation-dependent diseases. Such disorders may be diagnosed usingmethods known in the art.

Cancer

Cancer includes, in one embodiment, without limitation, leukemias (e.g.,acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia,acute myeloblastic leukemia, acute promyelocytic leukemia, acutemyelomonocytic leukemia, acute monocytic leukemia, acuteerythroleukemia, chronic leukemia, chronic myelocytic leukemia, chroniclymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin'sdisease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia,multiple myeloma, heavy chain disease, and solid tumors such as sarcomasand carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,glioblastoma multiforme (GBM, also known as glioblastoma),medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma,neurofibrosarcoma, meningioma, melanoma, neuroblastoma, andretinoblastoma).

In some embodiments, the cancer is glioma, astrocytoma, glioblastomamultiforme (GBM, also known as glioblastoma), medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma,melanoma, neuroblastoma, or retinoblastoma.

In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g.Grade I—Pilocytic Astrocytoma, Grade II—Low-grade Astrocytoma, GradeIII—Anaplastic Astrocytoma, or Grade IV—Glioblastoma (GBM)), chordoma,CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixedglioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma,metastatic brain tumor, oligodendroglioma, pituitary tumors, primitiveneuroectodermal (PNET) tumor, or schwannoma. In some embodiments, thecancer is a type found more commonly in children than adults, such asbrain stem glioma, craniopharyngioma, ependymoma, juvenile pilocyticastrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor,primitive neuroectodermal tumors (PNET), or rhabdoid tumor. In someembodiments, the patient is an adult human. In some embodiments, thepatient is a child or pediatric patient.

Cancer includes, in another embodiment, without limitation,mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, ovarian cancer, colon cancer, rectal cancer,cancer of the anal region, stomach cancer, gastrointestinal (gastric,colorectal, and duodenal), uterine cancer, carcinoma of the fallopiantubes, carcinoma of the endometrium, carcinoma of the cervix, carcinomaof the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, testicular cancer,chronic or acute leukemia, chronic myeloid leukemia, lymphocyticlymphomas, cancer of the bladder, cancer of the kidney or ureter, renalcell carcinoma, carcinoma of the renal pelvis, non-Hodgkins's lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocorticalcancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma,fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one ormore of the foregoing cancers.

In some embodiments, the cancer is selected from hepatocellularcarcinoma, ovarian cancer, ovarian epithelial cancer, or fallopian tubecancer; papillary serous cystadenocarcinoma or uterine papillary serouscarcinoma (UPSC); prostate cancer; testicular cancer; gallbladdercancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma;rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma;anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer;pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cellcarcinoma of the head and neck (SCCHN); salivary gland cancer; glioma,or brain cancer; neurofibromatosis-1 associated malignant peripheralnerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; ormedulloblastoma.

In some embodiments, the cancer is selected from hepatocellularcarcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovariancancer, ovarian epithelial cancer, fallopian tube cancer, papillaryserous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC),hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma,rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer,adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma,pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associatedmalignant peripheral nerve sheath tumors (MPNST), Waldenstrom'smacroglobulinemia, or medulloblastoma.

In some embodiments, the present invention provides a method fortreating a cancer that presents as a solid tumor, such as a sarcoma,carcinoma, or lymphoma, comprising the step of administering a disclosedcompound, or a pharmaceutically acceptable salt thereof, to a patient inneed thereof. Solid tumors generally comprise an abnormal mass of tissuethat typically does not include cysts or liquid areas. In someembodiments, the cancer is selected from renal cell carcinoma, or kidneycancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or livercancer; melanoma; breast cancer; colorectal carcinoma, or colorectalcancer; colon cancer; rectal cancer; anal cancer; lung cancer, such asnon-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC);ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, orfallopian tube cancer; papillary serous cystadenocarcinoma or uterinepapillary serous carcinoma (UPSC); prostate cancer; testicular cancer;gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bonesynovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewingsarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreaticcancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma;gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cellcarcinoma of the head and neck (SCCHN); salivary gland cancer; glioma,or brain cancer; neurofibromatosis-1 associated malignant peripheralnerve sheath tumors (MPNST); Waldenstrom's macroglobulinemia; ormedulloblastoma.

In some embodiments, the cancer is selected from renal cell carcinoma,hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma,colorectal cancer, colon cancer, rectal cancer, anal cancer, ovariancancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tubecancer, papillary serous cystadenocarcinoma, uterine papillary serouscarcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bonesynovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma,anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer,pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, braincancer, neurofibromatosis-1 associated malignant peripheral nerve sheathtumors (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is selected from hepatocellularcarcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovariancancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tubecancer, papillary serous cystadenocarcinoma, uterine papillary serouscarcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bonesynovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroidcancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductalcarcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1associated malignant peripheral nerve sheath tumors (MPNST),Waldenstrom's macroglobulinemia, or medulloblastoma.

In some embodiments, the cancer is hepatocellular carcinoma (HCC). Insome embodiments, the cancer is hepatoblastoma. In some embodiments, thecancer is colon cancer. In some embodiments, the cancer is rectalcancer. In some embodiments, the cancer is ovarian cancer, or ovariancarcinoma. In some embodiments, the cancer is ovarian epithelial cancer.In some embodiments, the cancer is fallopian tube cancer. In someembodiments, the cancer is papillary serous cystadenocarcinoma. In someembodiments, the cancer is uterine papillary serous carcinoma (UPSC). Insome embodiments, the cancer is hepatocholangiocarcinoma. In someembodiments, the cancer is soft tissue and bone synovial sarcoma. Insome embodiments, the cancer is rhabdomyosarcoma. In some embodiments,the cancer is osteosarcoma. In some embodiments, the cancer isanaplastic thyroid cancer. In some embodiments, the cancer isadrenocortical carcinoma. In some embodiments, the cancer is pancreaticcancer, or pancreatic ductal carcinoma. In some embodiments, the canceris pancreatic adenocarcinoma. In some embodiments, the cancer is glioma.In some embodiments, the cancer is malignant peripheral nerve sheathtumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1associated MPNST. In some embodiments, the cancer is Waldenstrom'smacroglobulinemia. In some embodiments, the cancer is medulloblastoma.

The present invention further features methods and compositions for thediagnosis, prognosis and treatment of viral-associated cancers,including human immunodeficiency virus (HIV) associated solid tumors,human papilloma virus (HPV)-16 positive incurable solid tumors, andadult T-cell leukemia, which is caused by human T-cell leukemia virustype I (HTLV-I) and is a highly aggressive form of CD4+ T-cell leukemiacharacterized by clonal integration of HTLV-I in leukemic cells (Seehttps://clinicaltrials.gov/ct2/show/study/NCT02631746); as well asvirus-associated tumors in gastric cancer, nasopharyngeal carcinoma,cervical cancer, vaginal cancer, vulvar cancer, squamous cell carcinomaof the head and neck, and Merkel cell carcinoma. (Seehttps://clinicaltrials.gov/ct2/show/study/NCT02488759; see alsohttps://clinicaltrials.gov/ct2/show/study/NCT0240886;https://clinicaltrials.gov/ct2/show/NCT02426892)

In some embodiments, the present invention provides a method fortreating a cancer in a patient in need thereof, comprising administeringto the patient any of the compounds, salts or pharmaceuticalcompositions described herein. In some embodiments, a cancer is any ofthe cancers described herein. In some embodiments, a cancer is melanomacancer. In some embodiments, a cancer is breast cancer. In someembodiments, a cancer is lung cancer. In some embodiments, a cancer issmall cell lung cancer (SCLC). In some embodiments, a cancer isnon-small cell lung cancer (NSCLC). In some embodiments, a cancer ismyeloma. In some embodiments, a cancer is multiple myeloma. In someembodiments, a cancer is hepatocellular carcinoma (HCC). In someembodiments, a cancer is bladder cancer. In some embodiments, a canceris kidney cancer. In some embodiments, a cancer is melanoma.

In some embodiments, the tumor is treated by arresting further growth ofthe tumor. In some embodiments, the tumor is treated by reducing thesize (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%,75%, 90% or 99% relative to the size of the tumor prior to treatment. Insome embodiments, tumors are treated by reducing the quantity of thetumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99%relative to the quantity of tumors prior to treatment.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acellular proliferative disorder. The exact amount required will varyfrom subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the disease or condition, theparticular agent, its mode of administration, and the like. Compounds ofthe invention are preferably formulated in dosage unit form for ease ofadministration and uniformity of dosage. The expression “dosage unitform” as used herein refers to a physically discrete unit of agentappropriate for the patient to be treated. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific effective dose levelfor any particular patient or organism will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “patient”, as used herein, means an animal, preferably a mammal,and most preferably a human.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the disease or disorder beingtreated. In certain embodiments, the compounds of the invention may beadministered orally or parenterally at dosage levels of about 0.01 mg/kgto about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg,of subject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

In some embodiment, the invention relates to a method of inducing ERstress in a biological sample comprising the step of contacting saidbiological sample with a compound of this invention, or a compositioncomprising said compound.

In some embodiment, the invention relates to a method of inducing the“unfolded protein response” (UPR) in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

In certain embodiments, the invention relates to a method of causingcalcium release from the endoplasmic reticulum (ER) via a putative Ca²⁺channel known as Wolframin (WFS1) in a biological sample comprising thestep of contacting said biological sample with a compound of thisinvention, or a composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Co-Administration of Additional Therapeutic Agents

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

In some embodiments, the additional therapeutic agent is selected froman immunostimulatory therapeutic compound. In some embodiments, theimmunostimulatory therapeutic compound is selected from elotuzumab,mifamurtide, an agonist or activator of a toll-like receptor, or anactivator of RORγt.

In some embodiments, the method further comprises administering to saidpatient a third therapeutic agent, such as an immune checkpointinhibitor. In some embodiments, the method comprises administering tothe patient in need thereof three therapeutic agents selected from acompound disclosed herein or a pharmaceutically acceptable salt thereof,an immunostimulatory therapeutic compound, and an immune checkpointinhibitor.

Other checkpoint inhibitors that may be used in the present inventioninclude OX40 agonists. OX40 agonists that are being studied in clinicaltrials include PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40antibody, in metastatic kidney cancer (NCT03092856) and advanced cancersand neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck & Co.), anagonistic anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357);MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, inadvanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, anagonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients withcolorectal cancer (NCT02559024), breast cancer (NCT01862900), head andneck cancer (NCT02274155) and metastatic prostate cancer (NCT01303705);and BMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody,in advanced cancers (NCT02737475).

Other checkpoint inhibitors that may be used in the present inventioninclude CD137 (also called 4-1BB) agonists. CD137 agonists that arebeing studied in clinical trials include utomilumab (PF-05082566,Pfizer) an agonistic anti-CD137 antibody, in diffuse large B-celllymphoma (NCT02951156) and in advanced cancers and neoplasms(NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-MyersSquibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer(NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

Other checkpoint inhibitors that may be used in the present inventioninclude CD27 agonists. CD27 agonists that are being studied in clinicaltrials include varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Other checkpoint inhibitors that may be used in the present inventioninclude glucocorticoid-induced tumor necrosis factor receptor (GITR)agonists. GITR agonists that are being studied in clinical trialsinclude TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, inmalignant melanoma and other malignant solid tumors (NCT01239134 andNCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, insolid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus),an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 andNCT03126110); MK-4166 (Merck & Co.), an agonistic anti-GITR antibody, insolid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), anagonistic hexameric GITR-ligand molecule with a human IgG1Fc domain, inadvanced solid tumors (NCT02583165).

Other checkpoint inhibitors that may be used in the present inventioninclude inducible T-cell co-stimulator (ICOS, also known as CD278)agonists. ICOS agonists that are being studied in clinical trialsinclude MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, inlymphomas (NCT02520791); GSK3359609 (Merck & Co.), an agonisticanti-ICOS antibody, in Phase 1 (NCT02723955); JTX-2011 (JounceTherapeutics), an agonistic anti-ICOS antibody, in Phase 1(NCT02904226).

Other checkpoint inhibitors that may be used in the present inventioninclude killer IgG-like receptor (KTR) inhibitors. KTR inhibitors thatare being studied in clinical trials include lirilumab(IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), an anti-KIRantibody, in leukemias (NCT01687387, NCT02399917, NCT02481297,NCT02599649), multiple myeloma (NCT02252263), and lymphoma(NCT01592370); IPH2101 (1-7F9, Innate Pharma) in myeloma (NCT01222286and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody thatbinds to three domains of the long cytoplasmic tail (KIR3DL2), inlymphoma (NCT02593045).

Other checkpoint inhibitors that may be used in the present inventioninclude CD47 inhibitors of interaction between CD47 and signalregulatory protein alpha (SIRPa). CD47/SIRPa inhibitors that are beingstudied in clinical trials include ALX-148 (Alexo Therapeutics), anantagonistic variant of (SIRPa) that binds to CD47 and preventsCD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621(SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion proteincreated by linking the N-terminal CD47-binding domain of SIRPa with theFc domain of human IgG1, acts by binding human CD47, and preventing itfrom delivering its “do not eat” signal to macrophages, is in clinicaltrials in Phase 1 (NCT02890368 and NCT02663518); CC-90002 (Celgene), ananti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9-G4 (FortySeven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782),acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

Other checkpoint inhibitors that may be used in the present inventioninclude CD73 inhibitors. CD73 inhibitors that are being studied inclinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, insolid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Other checkpoint inhibitors that may be used in the present inventioninclude agonists of stimulator of interferon genes protein (STING, alsoknown as transmembrane protein 173, or TMEM173). Agonists of STING thatare being studied in clinical trials include MK-1454 (Merck & Co.), anagonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); andADU-5100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Other checkpoint inhibitors that may be used in the present inventioninclude CSF1R inhibitors. CSF1R inhibitors that are being studied inclinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R smallmolecule inhibitor, in colorectal cancer, pancreatic cancer, metastaticand advanced cancers (NCT02777710) and melanoma, non-small cell lungcancer, squamous cell head and neck cancer, gastrointestinal stromaltumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855,Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410),melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Other checkpoint inhibitors that may be used in the present inventioninclude NKG2A receptor inhibitors. NKG2A receptor inhibitors that arebeing studied in clinical trials include monalizumab (IPH2201, InnatePharma), an anti-NKG2A antibody, in head and neck neoplasms(NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

In another aspect, the present invention provides a method of treatingcancer in a patient in need thereof, wherein said method comprisesadministering to said patient a compound disclosed herein or apharmaceutically acceptable salt thereof in combination with one or moreadditional therapeutic agents selected from an indoleamine(2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP)inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor.

In some embodiments, the IDO inhibitor is selected from epacadostat,indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906/KD108,or an enzyme that breaks down kynurenine.

In some embodiments, the PARP inhibitor is selected from olaparib,rucaparib, niraparib, iniparib, talazoparib, or veliparib.

In some embodiments, the HDAC inhibitor is selected from vorinostat,romidepsin, panobinostat, belinostat, entinostat, or chidamide.

In some embodiments, the CDK 4/6 inhibitor is selected from palbociclib,ribociclib, abemaciclib or trilaciclib.

In some embodiments, the method further comprises administering to saidpatient a third therapeutic agent, such as an immune checkpointinhibitor. In some embodiments, the method comprises administering tothe patient in need thereof three therapeutic agents selected from acompound disclosed herein or a pharmaceutically acceptable salt thereof,a second therapeutic agent selected from an indoleamine(2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP)inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4/CDK6inhibitor, or a phosphatidylinositol 3 kinase (PI3K) inhibitor, and athird therapeutic agent selected from an immune checkpoint inhibitor. Insome embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

Another immunostimulatory therapeutic that may be used in the presentinvention is recombinant human interleukin 15 (rhIL-15). rhIL-15 hasbeen tested in the clinic as a therapy for melanoma and renal cellcarcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453).Another immunostimulatory therapeutic that may be used in the presentinvention is recombinant human interleukin 12 (rhIL-12). Anothersuitable IL-15 based immunotherapeutic is heterodimeric IL-15 (hetIL-15,Novartis/Admune), a fusion complex composed of a synthetic form ofendogenous IL-15 complexed to the soluble IL-15 binding protein IL-15receptor alpha chain (IL15:sIL-15RA), which has been tested in Phase 1clinical trials for melanoma, renal cell carcinoma, non-small cell lungcancer and head and neck squamous cell carcinoma (NCT02452268).Recombinant human interleukin 12 (rhIL-12) has been tested in the clinicfor many oncological indications, for example, as a therapy for lymphoma(NM-IL-12, Neumedicines, Inc.), (NCT02544724 and NCT02542124).

In some embodiments, the PI3K inhibitor is selected from idelalisib,alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, orTGR1202.

In another aspect, the present invention provides a method of treatingcancer in a patient in need thereof, wherein said method comprisesadministering to said patient a compound disclosed herein or apharmaceutically acceptable salt thereof in combination with one or moreadditional therapeutic agents selected from a platinum-basedtherapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agentthat interferes with normal DNA synthesis, protein synthesis, cellreplication, or will otherwise inhibit rapidly proliferating cells.

In some embodiments, the platinum-based therapeutic is selected fromcisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, orsatraplatin.

In some embodiments, the taxane is selected from paclitaxel, docetaxel,albumin-bound paclitaxel, cabazitaxel, or SID530.

In some embodiments, the therapeutic agent that interferes with normalDNA synthesis, protein synthesis, cell replication, or will otherwiseinterfere with the replication of rapidly proliferating cells isselected from trabectedin, mechlorethamine, vincristine, temozolomide,cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate,asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrine,bendamustine, ixabepilone, nelarabine, clorafabine, trifluridine, ortipiracil.

In some embodiments, the method further comprises administering to saidpatient a third therapeutic agent, such as an immune checkpointinhibitor. In some embodiments, the method comprises administering tothe patient in need thereof three therapeutic agents selected from acompound disclosed herein or a pharmaceutically acceptable salt thereof,a second therapeutic agent selected from a platinum-based therapeutic, ataxane, a nucleoside inhibitor, or a therapeutic agent that interfereswith normal DNA synthesis, protein synthesis, cell replication, or willotherwise inhibit rapidly proliferating cells, and a third therapeuticagent selected from an immune checkpoint inhibitor.

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

In some embodiments, any one of the foregoing methods further comprisesthe step of obtaining a biological sample from the patient and measuringthe amount of a disease-related biomarker.

In some embodiments, the biological sample is a blood sample.

In some embodiments, the disease-related biomarker is selected fromcirculating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.

In one aspect, the present invention provides a method of treating anadvanced cancer, comprising administering a compound disclosed herein ora pharmaceutically acceptable salt thereof or pharmaceutical compositionthereof, either as a single agent (monotherapy), or in combination witha chemotherapeutic, a targeted therapeutic, such as a kinase inhibitor,and/or an immunomodulatory therapy, such as an immune checkpointinhibitor. In some embodiments, the immune checkpoint inhibitor is anantibody to PD-1. PD-1 binds to the programmed cell death 1 receptor(PD-1) to prevent the receptor from binding to the inhibitory ligandPDL-1, thus overriding the ability of tumors to suppress the hostanti-tumor immune response.

In some embodiments, the additional therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TKI258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In some embodiments, the additional therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. Approved mTOR inhibitors useful in the present invention includeeverolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); andsirolimus (Rapamune®, Pfizer).

In some embodiments, the additional therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful inthe present invention include olaparib (Lynparza®, AstraZeneca);rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro).Other PARP inhibitors being studied which may be used in the presentinvention include talazoparib (MDV3800/BMN 673/LT00673,Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290(BeiGene, Inc.).

In some embodiments, the additional therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. Approved PI3K inhibitorsuseful in the present invention include idelalisib (Zydelig®, Gilead).Other PI3K inhibitors being studied which may be used in the presentinvention include alpelisib (BYL719, Novartis); taselisib (GDC-0032,Genentech/Roche); pictilisib (GDC-0941, Genentech/Roche); copanlisib(BAY806946, Bayer); duvelisib (formerly IPI-145, InfinityPharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202(formerly RP5230, TG Therapeutics).

In some embodiments, the additional therapeutic agent is a proteasomeinhibitor. Approved proteasome inhibitors useful in the presentinvention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®,Amgen); and ixazomib (Ninlaro®, Takeda).

In some embodiments, the additional therapeutic agent is a histonedeacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in thepresent invention include vorinostat (Zolinza®, Merck & Co.); romidepsin(Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat(Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors beingstudied which may be used in the present invention include entinostat(SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide(Epidaza®, HBI-8000, Chipscreen Biosciences, China).

In some embodiments, the additional therapeutic agent is a CDKinhibitor, such as a CDK 4/6 inhibitor. Approved CDK 4/6 inhibitorsuseful in the present invention include palbociclib (Ibrance®, Pfizer);and ribociclib (Kisqali®, Novartis). Other CDK 4/6 inhibitors beingstudied which may be used in the present invention include abemaciclib(Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

In some embodiments, the additional therapeutic agent is an indoleamine(2,3)-dioxygenase (IDO) inhibitor. IDO inhibitors being studied whichmay be used in the present invention include epacadostat (INCB024360,Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib(INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer);BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); and anenzyme that breaks down kynurenine (Kynase, Kyn Therapeutics).

In some embodiments, the additional therapeutic agent is a growth factorantagonist, such as an antagonist of platelet-derived growth factor(PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

In some embodiments, the additional therapeutic agent is an aromataseinhibitor. Approved aromatase inhibitors which may be used in thepresent invention include exemestane (Aromasin®, Pfizer); anastazole(Arimidex®, AstraZeneca) and letrozole (Femara®, Novartis).

In some embodiments, the additional therapeutic agent is an antagonistof the hedgehog pathway. Approved hedgehog pathway inhibitors which maybe used in the present invention include sonidegib (Odomzo®, SunPharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, the additional therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, the additional therapeutic agent is a CC chemokinereceptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may beuseful in the present invention include mogamulizumab (Poteligeo®, KyowaHakko Kirin, Japan).

In some embodiments, the additional therapeutic agent is an isocitratedehydrogenase (IDH) inhibitor. IDH inhibitors being studied which may beused in the present invention include AG120 (Celgene; NCT02677922);AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer,NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, the additional therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, the additional therapeutic agent is a glutaminaseinhibitor. Glutaminase inhibitors being studied which may be used in thepresent invention include CB-839 (Calithera Biosciences).

In some embodiments, the additional therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/BiogenIdec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, the additional therapeutic agent is a topoisomeraseinhibitor. Approved topoisomerase inhibitors useful in the presentinvention include irinotecan (Onivyde®, Merrimack Pharmaceuticals);topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors beingstudied which may be used in the present invention include pixantrone(Pixuvri®, CTI Biopharma).

In some embodiments, the additional therapeutic agent is a nucleosideinhibitor, or other therapeutic that interfere with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells. Such nucleoside inhibitors or othertherapeutics include trabectedin (guanidine alkylating agent, Yondelis®,Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®,Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®,Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide(prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck& Co.); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, the additional therapeutic agent is aplatinum-based therapeutic, also referred to as platins. Platins causecross-linking of DNA, such that they inhibit DNA repair and/or DNAsynthesis, mostly in rapidly reproducing cells, such as cancer cells.Approved platinum-based therapeutics which may be used in the presentinvention include cisplatin (Platinol®, Bristol-Myers Squibb);carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer);oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®,Shionogi). Other platinum-based therapeutics which have undergoneclinical testing and may be used in the present invention includepicoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

In some embodiments, the additional therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. Approved taxane compounds which may be used in thepresent invention include paclitaxel (Taxol®, Bristol-Myers Squibb),docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical),albumin-bound paclitaxel (Abraxane®; Abraxis/Celgene), and cabazitaxel(Jevtana®, Sanofi-Aventis). Other taxane compounds which have undergoneclinical testing and may be used in the present invention include SID530(SK Chemicals, Co.) (NCT00931008).

In some embodiments, the additional therapeutic agent is an inhibitor ofanti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics whichmay be used in the present invention include venetoclax (Venclexta®,AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen). Othertherapeutic agents targeting apoptotic proteins which have undergoneclinical testing and may be used in the present invention includenavitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, the present invention provides a method of treatingprostate cancer comprising administering to a patient in need thereof aneffective amount of a compound disclosed herein or a pharmaceuticallyacceptable salt thereof or pharmaceutical composition thereof incombination with an additional therapeutic agent that interferes withthe synthesis or activity of androgens. Approved androgen receptorinhibitors useful in the present invention include enzalutamide(Xtandi®, Astellas/Medivation); approved inhibitors of androgensynthesis include abiraterone (Zytiga®, Centocor/Ortho); approvedantagonist of gonadotropin-releasing hormone (GnRH) receptor (degaralix,Firmagon®, Ferring Pharmaceuticals).

In some embodiments, the additional therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, the additional therapeutic agent is an inhibitor ofbone resorption. An approved therapeutic which inhibits bone resorptionis Denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, preventsbinding to its receptor RANK, found on the surface of osteoclasts, theirprecursors, and osteoclast-like giant cells, which mediates bonepathology in solid tumors with osseous metastases. Other approvedtherapeutics that inhibit bone resorption include bisphosphonates, suchas zoledronic acid (Zometa®, Novartis).

In some embodiments, the additional therapeutic agent is an inhibitor ofinteraction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, the additional therapeutic agent is an inhibitor oftransforming growth factor-beta (TGF-beta or TGFβ). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978.

Additional Co-Administered Therapeutic Agents—Targeted Therapeutics andImmunomodulatory Drugs

In some embodiments, the additional therapeutic agent is selected from atargeted therapeutic or immunomodulatory drug. Adjuvant therapies withtargeted therapeutics or immunomodulatory drugs have shown promisingeffectiveness when administered alone but are limited by the developmentof tumor immunity over time or evasion of the immune response.

In some embodiments, the present invention provides a method of treatingcancer, such as a cancer described herein, comprising administering to apatient in need thereof an effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof or pharmaceuticalcomposition thereof in combination with an additional therapeutic agentsuch as a targeted therapeutic or an immunomodulatory drug. In someembodiments, the immunomodulatory therapeutic specifically inducesapoptosis of tumor cells. Approved immunomodulatory therapeutics whichmay be used in the present invention include pomalidomide (Pomalyst®,Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®,LEO Pharma).

In other embodiments, the immunomodulatory therapeutic is a cancervaccine. In some embodiments, the cancer vaccine is selected fromsipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), which hasbeen approved for treatment of asymptomatic, or minimally symptomaticmetastatic castrate-resistant (hormone-refractory) prostate cancer; andtalimogene laherparepvec (Imlygic®, BioVex/Amgen, previously known asT-VEC), a genetically modified oncolytic viral therapy approved fortreatment of unresectable cutaneous, subcutaneous and nodal lesions inmelanoma. In some embodiments, the additional therapeutic agent isselected from an oncolytic viral therapy such as pexastimogenedevacirepvec (PexaVec/JX-594, SillaJen/formerly JennerexBiotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virusengineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755)and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech),a variant of respiratory enteric orphan virus (reovirus) which does notreplicate in cells that are not RAS-activated, in numerous cancers,including colorectal cancer (NCT01622543); prostate cancer(NCT01619813); head and neck squamous cell cancer (NCT01166542);pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer(NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly knownas ColoAdl), an adenovirus engineered to express a full length CD80 andan antibody fragment specific for the T-cell receptor CD3 protein, inovarian cancer (NCT02028117); metastatic or advanced epithelial tumorssuch as in colorectal cancer, bladder cancer, head and neck squamouscell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102(Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF,in melanoma (NCT03003676); and peritoneal disease, colorectal cancer orovarian cancer (NCT02963831); GL-ONC1 (GLV-1 h68/GLV-1 h153, GeneluxGmbH), vaccinia viruses engineered to express beta-galactosidase(beta-gal)/beta-glucoronidase or beta-gal/human sodium iodide symporter(hNIS), respectively, were studied in peritoneal carcinomatosis(NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); orCG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, inbladder cancer (NCT02365818).

In some embodiments, the additional therapeutic agent is selected fromJX-929 (SillaJen/formerly Jennerex Biotherapeutics), a TK- and vacciniagrowth factor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8+ T cell response.

In some embodiments, the present invention comprises administering tosaid patient a compound disclosed herein or a pharmaceuticallyacceptable salt thereof in combination with a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June; hereby incorporated byreference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

Additional Co-Administered Therapeutic Agents—Immunostimulatory Drugs

In some embodiments, the additional therapeutic agent is animmunostimulatory drug. For example, antibodies blocking the PD-1 andPD-L1 inhibitory axis can unleash activated tumor-reactive T cells andhave been shown in clinical trials to induce durable anti-tumorresponses in increasing numbers of tumor histologies, including sometumor types that conventionally have not been considered immunotherapysensitive. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14,1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibodynivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538,MDX1106 and BMS-936558), has shown potential to improve the overallsurvival in patients with RCC who had experienced disease progressionduring or after prior anti-angiogenic therapy.

In some embodiments, the present invention provides a method of treatingcancer, such as a cancer described herein, comprising administering to apatient in need thereof an effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof or pharmaceuticalcomposition thereof in combination with an additional therapeutic agentsuch as a immunostimulatory drug, such as an immune checkpointinhibitor. In some embodiments, the compound and the checkpointinhibitor are administered simultaneously or sequentially. In someembodiments, a compound disclosed herein is administered prior to theinitial dosing with the immune checkpoint inhibitor. In certainembodiments, the immune checkpoint inhibitor is administered prior tothe initial dosing with the compound disclosed herein.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In someembodiments, a compound disclosed herein or a pharmaceuticallyacceptable salt thereof is administered in combination with nivolumab(anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab(anti-PD-1 antibody, Keytruda®, Merck & Co.); ipilimumab (anti-CTLA-4antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-L1 antibody,Tecentriq®, Genentech).

Other immune checkpoint inhibitors suitable for use in the presentinvention include REGN2810 (Regeneron), an anti-PD-1 antibody tested inpatients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540);cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662);and melanoma (NCT03002376); pidilizumab (CureTech), also known asCT-011, an antibody that binds to PD-1, in clinical trials for diffuselarge B-cell lymphoma and multiple myeloma; avelumab (Bavencio®,Pfizer/Merck KGaA), also known as MSB0010718C), a fully human IgG1anti-PD-L1 antibody, in clinical trials for non-small cell lung cancer,Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovariancancer, bladder cancer, head and neck cancer, and gastric cancer; andPDR001 (Novartis), an inhibitory antibody that binds to PD-1, inclinical trials for non-small cell lung cancer, melanoma, triplenegative breast cancer and advanced or metastatic solid tumors.Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonalantibody against CTLA-4 that has been in studied in clinical trials fora number of indications, including: mesothelioma, colorectal cancer,kidney cancer, breast cancer, lung cancer and non-small cell lungcancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cellcancer, squamous cell cancer of the head and neck, hepatocellularcarcinoma, prostate cancer, endometrial cancer, metastatic cancer in theliver, liver cancer, large B-cell lymphoma, ovarian cancer, cervicalcancer, metastatic anaplastic thyroid cancer, urothelial cancer,fallopian tube cancer, multiple myeloma, bladder cancer, soft tissuesarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody thatis being studied in Phase 1 clinical trials for advanced solid tumors(NCT02694822).

Another paradigm for immune-stimulation is the use of oncolytic viruses.In some embodiments, the present invention provides a method fortreating a patient by administering a compound disclosed herein or apharmaceutically acceptable salt thereof or pharmaceutical compositionthereof in combination with an immunostimulatory therapy such asoncolytic viruses. Approved immunostimulatory oncolytic viruses whichmay be used in the present invention include talimogene laherparepvec(live, attenuated herpes simplex virus, Imlygic®, Amgen).

In some embodiments, the additional therapeutic agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. An activator of RORγt, that isbeing studied which may be used in the present invention is LYC-55716(Lycera), which is currently being evaluated in clinical trials for thetreatment of solid tumors (NCT02929862).

In some embodiments, the additional therapeutic agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other checkpoint inhibitors that may be used in the present inventioninclude inhibitors of T-cell immunoglobulin mucin containing protein-3(TIM-3). TIM-3 inhibitors that may be used in the present inventioninclude TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3antibody which is being studied in solid tumors (NCT02817633). LY3321367(Eli Lilly) is an anti-TIM-3 antibody which is being studied in solidtumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody whichis being studied in advanced malignancies (NCT02608268).

Other checkpoint inhibitors that may be used in the present inventioninclude inhibitors of T cell immunoreceptor with Ig and ITIM domains, orTIGIT, an immune receptor on certain T cells and NK cells. TIGITinhibitors that may be used in the present invention include BMS-986207(Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313);OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

Checkpoint inhibitors that may be used in the present invention alsoinclude inhibitors of Lymphocyte Activation Gene-3 (LAG-3). LAG-3inhibitors that may be used in the present invention include BMS-986016and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), ananti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma(NCT02658981). REGN3767 (Regeneron), is also an anti-LAG-3 antibody, andis being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) isan LAG-3-Ig fusion protein, being studied in melanoma (NCT02676869);adenocarcinoma (NCT02614833); and metastatic breast cancer(NCT00349934).

Other immune-oncology agents that may be used in the present inventionin combination with a compound disclosed herein include urelumab(BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody;varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonalantibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonalantibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-MyersSquibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, InnatePharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab(GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck &Co.), an anti-GITR monoclonal antibody.

Other additional therapeutic agents that may be used in the presentinvention include glembatumumab vedotin-monomethyl auristatin E (MMAE)(Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked tothe cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumortypes associated with cancer cells' ability to metastasize.

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to checkpointinhibitors; aromatase inhibitors; antiestrogens; topoisomerase Iinhibitors; topoisomerase II inhibitors; microtubule active compounds;alkylating compounds; histone deacetylase inhibitors; compounds whichinduce cell differentiation processes; cyclooxygenase inhibitors; MMPinhibitors; mTOR inhibitors; antineoplastic antimetabolites; platincompounds; compounds targeting/decreasing a protein or lipid kinaseactivity and further anti-angiogenic compounds; compounds which target,decrease or inhibit the activity of a protein or lipid phosphatase;gonadorelin agonists; anti-androgens; methionine aminopeptidaseinhibitors; matrix metalloproteinase inhibitors; bisphosphonates;biological response modifiers; antiproliferative antibodies; heparanaseinhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors;proteasome inhibitors; compounds used in the treatment of hematologicmalignancies; compounds which target, decrease or inhibit the activityof Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin,NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (Temodal©); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signalling processes should proceed.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MEDI4736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™ Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™). The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™) daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aP13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib.

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDCl25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin(17AAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4^(th) Edition, Vol. 1,pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives. Also included are inparticular those compounds, proteins or monoclonal antibodies of VEGFsuch as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or apharmaceutically acceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; Zd₆474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Biomarkers

The invention also provides methods of predicting the likelihood ofresponse of a patient to an anticancer treatment with a compound of theinvention described herein or a pharmaceutically acceptable saltthereof. In some embodiments, the methods comprise measuring a level ofendoplasmic reticulum (ER) stress or unfold protein response (UPR) in atumor of the patient. Without being bound to a particular theory, ERstress may generate UPR. ER stress or UPR can be caused by, for example,disruption of intracellular calcium homeostasis, disruption ofglycosylation, and/or disruption of nutrient availability. In someembodiments, measuring a level of ER stress or unfold protein responseis performed prior to the anticancer treatment. In some embodiments, thelevel of ER stress or unfolded protein response is a level of Wolframsyndrome 1 (WFS1) or the protein encoded by WFS1.

WFS1 is a gene expressing the wolframin protein. In some embodiments,the protein encoded by WFS1 is wolframin. WFS1 (gene ID 7466, accessionnumber AF084481) encodes the protein wolframin (accession numberAAC64943) which is a transmembrane protein that resides in the ER andplays a role in regulating calcium homeostasis.

In some embodiments, methods of predicting the likelihood of response ofa patient to an anticancer treatment with a compound of the inventiondescribed herein or a pharmaceutically acceptable salt thereof furthercomprise determining whether to treat the patient with a compound of theinvention described herein or a pharmaceutically acceptable saltthereof, wherein the patient will be treated with the compound if thelevel of WFS1 or the protein encoded by WFS1 is greater than a referencevalue from a patient with the same cancer. The “reference value from apatient with the same cancer” is a cut-off value (cut-off point orstandard value) for WFS1 or protein encoded by WFS1 expression levels orscores thereof (e.g., mRNA copies or immunohistochemistry stainingdensity, or a combination thereof).

The invention also provides methods of treating a patient with cancer,comprising: measuring an expression level of WFS1 or the protein encodedby WFS1 in a tumor of the patient; and administering a pharmaceuticallyeffective amount of a compound of the invention to the patient if saidexpression level of WFS1 or the protein encoded by WFS1 is greater thana reference value from a patient with the same cancer. In someembodiments, the methods further comprise administering apharmaceutically effective amount of a compound of the invention,wherein an expression level of WFS1 or the protein encoded by WFS1 in atumor of the patient is greater than a reference value from a patientwith the same cancer.

The invention also provides in vitro methods for predicting thelikelihood of response of a patient to an anticancer treatment with acompound of the invention. The methods comprise a) measuring anexpression level of ER stress or unfold protein response in a tumorsample obtained form the patient. In some embodiments, the expressionlevel of ER stress or unfolded protein response is a level of WFS1 orthe protein encoded by WFS1. In some embodiments, the methods furthercomprise b) applying the expression levels of ER stress or unfoldprotein response in a tumor sample obtained form the patient to amathematical equation in order to calculate a patient expression score;and c) comparing the patient expression score to a reference level; andidentifying the patient as more likely to respond to the anticancertreatment with a compound of the invention is above the reference level.In some embodiments, a patient signature score above the reference levelindicates a patient's high likelihood to respond to treatment with acompound of the invention, whereas a patient signature score below thereference level indicates that said patient is less likely to respond tothat treatment. The tumor samples can be any suitable samples taken froma patient. Examples include blood, plasma, and biopsy samples.

The expression level of ER stress or unfold protein response, such asthe expression level of WFS1 or the protein encoded by WFS1, can bemeasured by any method known in the art, such as RT-PCR, northernhybridization, ELISA, immunohistochemistry, and/or immunoblotting. Insome embodiments, the expression level of WFS1 is an mRNA expressionlevel. RNA sequencing or microarray measurements (e.g., GeneChip HumanGenome U133 Plus 2.0 Array) can also be employed for measuring mRNAexpression levels.

In some embodiments, the patient expression score can be calculated fromthe sum of log 2-transformed mRNA expression levels measured prior totreatment. In some embodiments, the patient expression score iscalculated based on mRNA expression levels obtained by RT PCRmeasurements. The patient expression score calculated using RT PCR maybe different from the value calculated based on the microarraytechnology. However, the patient expression score based on RT PCR can beconverted into the value obtained when using microarray technology byestablished correlation between these methods, as well known to theperson of skill in the art.

The invention also provides kits and devices for predicting thelikelihood of response of a patient to an anticancer treatment with acompound of the invention. The kits or devices comprise a) reagents tomeasure an expression level of WFS1 or the protein encoded by WFS1 in atumor of the patient; and b) a guideline comprising instructions aboutwhether or not a patient would respond to an anticancer treatment with acompound of the invention, wherein an expression level of WFS1 or theprotein encoded by WFS1 greater than a reference value from a patientwith the same cancer indicates that the patient is likely to respond tothe anticancer treatment. The guideline can be a comparator module whichcomprises a reference value or a set of reference values to which thelevel of WFS1 in the sample is compared. The comparator module can be inany suitable form. In some embodiments, it is in the form a displaydevice, for example, a strip of colour or numerically coded materialwhich is designed to be placed next to the readout of the samplemeasurement to indicate the response levels. In some embodiments, theexpression level of WFS1 or the protein encoded by WFS1 in the tumor ofa patient with cancer is used to predict the likelihood of response ofthat patient to the compounds of the invention described herein.

EXEMPLIFICATION General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Unless otherwisestated, one or more tautomeric forms of compounds of the examplesdescribed hereinafter may be prepared in situ and/or isolated. Alltautomeric forms of compounds of the examples described hereafter shouldbe considered to be disclosed. Temperatures are given in degreescentigrade. If not mentioned otherwise, all evaporations are performedunder reduced pressure, preferably between about 15 mm Hg and 100 mm Hg(=20-133 mbar). The structure of final products, intermediates andstarting materials is confirmed by standard analytical methods, e.g.,microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR.Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

Example 1: Preparation of Intermediates List of Abbreviations

The following abbreviations are used in the examples below:

-   Ac acetyl-   AcOH acetic acid-   Ac₂O acetic anhydride-   aq aqueous-   ATP adenosine triphosphate-   BF₃.OEt₂ boron trifluoride diethyl ether-   Bn benzyl-   Br₂ Bromine-   ACN, CH₃CN acetonitrile-   CD₃OD methanol-d₄-   CDCl₃ chloroform-d-   COD 1,5-cyclooctadiene-   Conc. concentrate-   Cs₂CO₃ cesium carbonate-   CuI copper(I) iodide-   CuSO₄ copper(II) sulfate-   CV column volume-   CA commercially available-   ° C. degree Celcius-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCM methylene chloride or dichloromethane-   DIPEA N,N-diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   DMSO-d6 deutered dimethylsulfoxide-   EA ethylacetate-   Equiv equivalent-   EtOAc ethyl acetate-   g gram(s)-   HATU    O-(7-azabenzotriazol-1-yl),N,N,N″,N″-tetramethyluroniumhexafluorophosphate-   h hour(s)-   HCl hydrochloric acid-   Hex hexanes-   HPLC high pressure liquid chromatography-   LCMS liquid chromatography mass spectrometry-   M molar-   MHz megahertz-   mg milligram(s)-   mL milliliter(s)-   mM millimolar-   MeOH methanol-   MeONa sodium methoxide-   min minute(s)-   MS mass spectrometer-   MTBE methyl tert-butyl ether-   μM micromolar-   N normal (molar) concentration-   ¹H NMR proton nuclear magnetic resonance-   NMO N-methylmorpholine-N-oxide-   ON overnight-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   Pd/C palladium on carbon-   Pd(OH)₂ dihydroxy palladium-   t-butyl X-phos    2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl-   psi pound per square inch-   Py pyridine-   r.b.f. (rbf) round bottom flask-   RT (rt or r. t.) room temperature-   S-Phos 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-   TBAF tetrabutylammonium fluoride-   TBDMSOTf tert-butyldimethylsilyl trifluoromethanesulfonate-   TBS tert-butyldimethylsilyl-   TEA triethylamine-   Tf trifluoromethanesulfonyl-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMS trimethylsilyl-   TMSI trimethylsilyl iodide-   TMSN₃ trimethylsilyl azide-   TMSOTf trimethylsilyl trifluoromethanesulfonate-   TPAP Tetrapropylammonium perruthenate-   UPLC ultra performance liquid chromatography

A. Dihydropteridin-one Intermediates Preparation

A-1. (7S)-2-Chloro-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

2,4-Dichloropyrimidin-5-amine (30 g, 159.4 mmol),(2S)-2-(methylamino)propanoic acid (29.59 g, 286.9 mmol), and sodiumbicarbonate (48.20 g, 573.8 mmol) were taken into EtOH (285 mL) andwater (15.00 mL) and heated to 80° C. for 3 hours. The reaction wascooled to room temperature then cooled in an ice bath. The precipitatewas collected by vacuum filtration and washed with water. The filtercake was suspended in water and stirred for 1 hour at room temperature.The solids were collected, washed with water, and dried overnight in avacuum oven at 50° C. to provide 26 g (75% yield) of the desiredproduct. ¹H NMR (300 MHz, DMSO-d6) δ 10.76 (s, 1H), 7.50 (s, 1H), 4.19(q, J=6.9 Hz, 1H), 2.99 (s, 3H), 1.33 (d, J=6.9 Hz, 3H); ESMS(M+H)=212.95; Chiral HPLC—99% ee (AD-H column; 30% (1:1 Et OH/MeOH) inheptane): Rt=6.052 mins. (99.3% ee); [α]_(D)=±16.21 (c=1.03, MeOH).

A-2. (7S)-2-Chloro-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

2,4-Dichloro-6-methyl-pyrimidin-5-amine (200 g, 1.123 mol),(2S)-2-(methylamino)propanoic acid (208.4 g, 2.021 mol), and sodiumbicarbonate (339.6 g, 4.043 mol) were taken into EtOH (1.900 L) andwater (100.0 mL), and heated to reflux overnight. The mixture was cooledto room temperature. The resulting precipitate was filtered and washedthree times with water. The filter cake was taken into water (2 L), andstirred for 0.5 h. The solid was collected by vacuum filtration, washedwith EtOH (2×300 ml), and dried under vacuum at 50° C. overnight toprovide the product as an off-white solid, 196.7 g, 77% yield. ChiralHPLC: (Chiralpak AD-Hcolumn, 20% EtOH/hex, 20 min run, 98% ee. ¹H NMR(300 MHz, DMSO-d6) δ 10.39 (s, 1H), 4.21 (q, J=6.8 Hz, 1H), 3.00 (s,3H), 2.25 (s, 3H), 1.30 (d, J=6.9 Hz, 3H). ESMS (M+H)=227.04;[α]_(D)=+40.42° (c=1, MeOH/DCM 1/4). The R-isomer of A-2:[α]_(D)=−42.42° (c=1, DMSO).

A-3. (7S)-2-Chloro-4,5,7,8-tetramethyl-7H-pteridin-6-one

(7S)-2-Chloro-4,7,8-trimethyl-5,7-dihydropteridin-6-one (118 g, 521mmol) and potassium carbonate (107.9 g, 791 mmol) were taken into 1.5 Lof DMF and cooled to 0° C. Iodomethane 32.4 ml, 520.6 mmol) was added tothe reaction mixture and the reaction was warmed to room temperature.

The reaction was poured into 4.5 L of water and extracted with ethylacetate (2×1.5 L). The extracts were combined and dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to afford the crudeproduct. The crude product was purified by column chromatography (1.5 kgSiO₂) and eluted with a gradient of 5-80% ethyl acetate in hexanes. Thedesired fractions were combined and evaporated in vacuo to provide thedesired product, wt. 99 g. Chiral HPLC (IC column, 40% ethanol/hexane,20 mins run.) Rt=3.983 mins. (99% ee); ¹H NMR (300 MHz, CDCl₃) δ 4.11(q, J=6.9 Hz, 1H), 3.35 (s, 3H), 3.11 (s, 3H), 2.50 (s, 3H), 1.25 (d,J=6.9 Hz, 3H); ESMS (M+1)=241.18; [α]_(D)=−73.5° (c=1, methanol).

A-4. (7S)-2-Chloro-8-isopropyl-4,7-dimethyl-5,7-dihydropteridin-6-one

Step 1: Methyl (2S)-2-(isopropylamino)propanoate

To a mixture of methyl (2S)-2-aminopropanoate (Hydrochloric Acid (2.8 g,20.06 mmol) in MeOH (60 mL) and acetone (10 mL, 136.2 mmol) was added10% Pd/C (642.0 mg, 0.6033 mmol), followed by 3 drops ofN-methylmorpholine. The mixture was hydrogenated under hydrogen at 50psi overnight. The reaction was filtered through celite and the filtrateevaporated in vacuo. The residue was taken into 100 mL of ethyl acetateand stirred for 10 minutes. The white solid was collected by vacuum toprovide the title product, wt. 2.8 g (77% yield). [α]_(D)=3.3° (c=1,methanol). ¹H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.11 (s, 1H), 4.19(d, J=6.8 Hz, 1H), 3.77 (s, 3H), 3.35 (t, J=6.2 Hz, 1H), 1.48 (d, J=7.1Hz, 3H), 1.26 (t, J=6.3 Hz, 6H). ESMS (M+1)=146.15.

Step 2: (7S)-2-Chloro-8-isopropyl-4,7-dimethyl-5,7-dihydropteridin-6-one

Methyl (2S)-2-(isopropylamino)propanoate hydrochloride (1.41 g, 7.762mmol) was suspended in 10 mL of cyclohexane and neutralized with 2M NaOH(4.4 ml, 8.800 mmol). The organic layer was separated and added to asolution of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (1.6 g, 7.7 mmol)and NaHCO₃ (2.6 g, 30.9 mmol) in 40 mL of cyclohexane. The mixture washeated to reflux equipped with a Dean-Stark trap to remove water. After4 hours, the mixture was hot-filtered through celite and washed withdichloromethane. The filtrate was evaporated in vacuo. The residue wasdissolved in THE (20 mL). Platinum (Strem 78-1614, 3% wt, 506 mg, 0.078mmol) and bis[(E)-1-methyl-3-oxo-but-1-enoxy]-oxo-vanadium (103 mg,0.388 mmol) was added to the mixture and hydrogenated with hydrogen at50 psi for 18 hours. The reaction was filtered through Celite, thefiltrate evaporated in vacuo. The crude product was purified by columnchromatography (SiO₂) eluting with a gradient of 0-80% ethyl acetate indichloromethane to provide the title compound as a white solid, wt. 600mg (30.5% yield). ¹H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 4.58-4.41(m, 1H), 4.25 (q, J=6.7 Hz, 1H), 2.27 (s, 3H), 1.37-1.15 (m, 9H). ESMS(M+1)=255.07.

A-5. 2-Chloro-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

2,4-dichloro-6-methyl-pyrimidin-5-amine (5 g, 28.09 mmol),2-methylaminoacetic acid (2.503 g, 28.09 mmol), and NaHCO₃ (8.493 g,101.1 mmol) were taken into 20 ml of 95% ethanol. The reaction wasrefluxed for 4 days then cooled and poured onto ice and stirred. Theprecipitate was collected and washed well with water. The filter cakewas placed in a flask and stirred in 100 ml of water, filtered, washedwell with water and ethanol then dried under vacuum at 55° C. for 24hours to provide the desired product, wt. 5.2 g. ¹H NMR (300 MHz,DMSO-d6) δ 10.35 (s, 1H), 4.11 (s, 2H), 2.96 (s, 3H), 2.23 (s, 3H);

A-6.(7S)-2-Chloro-7-cyclopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1: Methyl(S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopropylacetate

To a solution of (S)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-aceticacid (408 g, 1.896 mol) and silver(I) oxide (879 g, 3.792 mol) in DMF (5L) at 10° C. was added iodomethane (550 ml, 8.835 mol)) dropwise over 2hours. The mixture was allowed to warm to room temperature then heatedat 45° C. for 18 hours. The reaction mixture was cooled to roomtemperature and filtered over Celite. The Celite pad was washed with 1 Lof methyl t-butyl ether (MTBE). The filtrate was diluted with 8 L ofMTBE and washed with 4 L of 0.5 M sodium thiosulfate. The organic layerwas washed brine, dried over anhydrous magnesium sulfate, andconcentrated in vacuo to provide the title product as a colorless oil,wt. 431.99 g (93.6% yield). 1H NMR (300 MHz, CDCl₃) δ 3.94 (d, J=23.5Hz, 0.5H), 3.74 (s, 3H), 3.52 (d, J=14.5 Hz, 0.5H), 2.98 (d, J=7.9 Hz,3H), 1.45 (s, 9H), 1.20 (s, 1H), 0.82-0.68 (m, 1H), 0.57 (s, 2H),0.42-0.28 (m, 1H)

Step 2: Methyl (S)-2-amino-2-cyclopropylacetate hydrochloride

To a cooled (10° C.) solution of methyl(S)-2-((tert-butoxycarbonyl)(methyl)amino)-2-cyclopropyl acetate (431.9g, 1.775 mol)) in dichloromethane (750 mL) was added a 4 M HCl (3 L, 12mol). The reaction was allowed to warm to room temperature and stirredovernight (˜18 hours). The reaction was concentrated in vacuo and theresulting residue triturated with MTBE. The resulting white solid wascollected under vacuum and dried to provide the title product, wt.286.85 g (89.95% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 2H), 3.76(s, 3H), 3.48 (dd, J=14.1, 7.4 Hz, 1H), 2.59 (s, 3H), 1.23-1.07 (m, 1H),0.80-0.60 (m, 3H), 0.55-0.41 (m, 1H).

Step 3: Methyl2-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)-2-cyclopropylacetate

In a 3-neck 12 L flask equipped with a Dean Stark trap was added amixture of methyl (S)-2-amino-2-cyclopropylacetate hydrochloride (286.85g, 1.597 mol), 2,4-dichloro-6-methyl-5-nitro-pyrimidine (316.3 g, 1.521mol), and sodium bicarbonate (636.3 g, 7.574 mol) in cyclohexane (3.8L). The mixture was refluxed for 3 hours. The mixture was allowed tocool to 70° C. and filtered through a pad of Celite then washed with 2 Lof hot cyclohexane. The filtrate was concentrated in vacuo to provide aviscous oil that contained a ppt. The oil was redissolved in cyclohexaneand filtered through Celite. The filtrate was concentrated in vacuo toprovide the product as a clear yellow viscous oil, wt. 498.56 g. Somecyclohexane solvent still present. Product yield was assumed to bequantitative. 1H NMR (300 MHz, CDCl₃) δ 4.35 (d, J=9.9 Hz, 1H), 3.80 (s,3H), 3.04 (s, 3H), 2.47 (s, 3H), 1.36-1.23 (m, 1H), 0.89 (tdd, J=13.3,6.4, 5.0 Hz, 1H), 0.78-0.65 (m, 2H), 0.50-0.35 (m, 1H). ESMS(M+1)=+315.0.

Step 4:(7S)-2-Chloro-7-cyclopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

A suspension of Methyl2-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)-2-cyclopropylacetate(478.7 g, 1.521 mol) and Pt/C (50 g, 7.69 mmol) was shaken on a Parrapparatus under 40 psi of hydrogen for 6 hours. VO(acac)₂ (40 g, 150.9mmol) was added to the reaction and the reaction shaken overnight under35 psi of hydrogen. The reaction was filtered through a pad of Celite ontop of Florisil. The filter pad was washed with a 1:1 mixture ofdichloromethane/methanol (2 L) then 1.5 L of methanol. The filtrate wasconcentrated to ˜ 1 L and a tan precipitate formed. The precipitate wascollected by vacuum filtration and washed well with heptane to providean off-white solid. The solid was dried under vacuum to provide thetitle product, wt. 278.69 g, 72.5% yield. 1H NMR (300 MHz, DMSO-d6) δ10.43 (s, 1H), 3.54 (d, J=9.1 Hz, 1H), 3.09 (s, 3H), 2.27 (s, 3H), 0.95(tdd, J=9.0, 6.7, 3.5 Hz, 1H), 0.57 (tdd, J=7.4, 5.9, 1.3 Hz, 2H),0.52-0.33 (m, 2H); ESMS (M+1)=253.23. [α]^(22.9) _(D)=−5 1. 2 3 (c=1,DMSO).

A-7. 2-Chloro-4,8-dimethyl-7-propyl-7,8-dihydropteridin-6(5H)-one

2,4-dichloro-6-methyl-pyrimidin-5-amine (2 g, 11.23 mmol),2-(methylamino)pentanoic acid (1.915 g, 14.60 mmol), and sodiumbicarbonate (3.396 g, 40.43 mmol) were taken into 20 ml of 95% ethanol.The reaction was refluxed for 4 days then cooled and poured onto ice andstirred. The solid was collected and washed well with water. The filtercake was placed in a flask and stirred in the present of 300 ml ofwater. This was washed well with water and ethanol then dried undervacuum at 55° C. for 24 hours to provide the title product wt. 2.05 g(71.7% yield); 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 4.21 (dd,J=6.2, 4.2 Hz, 1H), 3.01 (s, 3H), 2.24 (s, 3H), 1.89-1.64 (m, 2H), 1.17(q, J=7.5 Hz, 2H), 0.85 (t, J=7.2 Hz, 3H). ESMS (M+1)=255.14.

A-8. (7S)-2-Chloro-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

(2S)-2-(methylamino)butanoic acid trifluoroacetate salt (7.939 g, 23mmol), 2,4-dichloro-6-methyl-pyrimidin-5-amine (3 g, 16.85 mmol) andsodium bicarbonate (7.078 g, 84.25 mmol) were taken into 95% EtOH (95mL) and heated to reflux for 20 hours. The reaction was cooled to roomtemperature and 1N HCl was used to neutralize the solution to pH 6. Theaqueous mixture was extracted with dichloromethane (3×30 ml). Thecombined organic extracts were washed with water, dried over anhydroussodium sulfate, filtered and evaporated to provide an off white solidthat was purified by column chromatography (SiO₂) eluting with agradient of 0-20% methanol/dichloromethane to provide the title productas a white solid. 1H NMR (300 MHz, CDCl₃) δ 8.35 (s, 1H), 4.16 (dd,J=6.3, 3.6 Hz, 1H), 3.13 (s, 3H), 2.33 (s, 3H), 2.02 (td, J=7.3, 3.6 Hz,1H), 1.94-1.76 (dq, 1H), 0.91 (t, J=7.5 Hz, 3H); [α]_(D)=+46.6°(chloroform; c=1)

A-9.(7S)-2-Chloro-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared following the procedure used for IntermediateA-6 (step 3 & 4) by reaction of dichloro-6-methyl-5-nitro-pyrimidine (25g, 120 mmol) and methyl methyl-L-valinate (24.02 g, 132.2 mmol) followedby reduction and cyclization to provide the title product, wt. 22.81 g(72% overall yield). 1H NMR (300 MHz, CDCl₃) δ 9.46 (s, 1H), 3.98 (d,J=4.1 Hz, 1H), 3.19 (s, 3H), 2.38 (s, 3H), 2.34-2.18 (m, 1H), 1.10 (d,J=7.0 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H); ESMS (M+1)=255.12;[α]_(D)=+66.24° (chloroform; c=1).

A-10.(7S)-2-Chloro-5,8-dimethyl-7-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-oneStep 1: (7S)-2-Chloro-7-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-one

2,4-Dichloro-5-amino-pyrimidine (1 g, 6.1 mmol),(2S)-2-aminopent-4-ynoic acid (1.035 g, 9.15 mmol), anddiisopropylethylamine (3.2 mL, 18.29 mmol) were taken into ethanol (10mL) and heated to 120° C. for 22 hours. The reaction was cooled to roomtemperature and a precipitate formed that was collected by vacuumfiltration and washed well with ethanol to provide the desired product,wt. 780 mg (57% yield); ESMS (M+1)=233.08

Step 2:(7S)-2-Chloro-5,8-dimethyl-7-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-one

Iodomethane (335 μl, 5.39 mmol) was added to a mixture of(7S)-2-Chloro-7-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-one (500 mg,2.25 mmol) and cesium carbonate (2.2 g, 6.74 mmol) in DMF (5 ml) andstirred at room temperature for 20 hours. The reaction was poured intowater (50 ml) and extracted with ethyl acetate (3×100 ml). The combinedextracts were washed with water (2×25 ml) and brine (25 ml), dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo to providetitle product. Wt. 400 mg (71% yield); ESMS (M+1)=251.09.

A-11. 2-Chloro-4,7,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

2-Methyl-2-(methylamino)propanoic acid (2 g, 17.07 mmol),2,4-dichloro-6-methyl-pyrimidin-5-amine (2 g, 11.23 mmol), and sodiumcarbonate (1.190 g, 11.23 mmol) were taken into n-butanol (15 mL) andheated in a microwave to 165° C. for 75 minutes. The reaction was cooledto room temperature and the solvent was evaporated in vacuo. Water wasadded to the residue and a precipitate formed. This was collected byvacuum filtration and washed well with water to provide 650 mg of thedesired product. The aqueous filtrate was extracted with ethyl acetate(3×100 ml). The extracts were combined, dried over sodium sulfate,filtered, and evaporated in vacuo to provide 1.3 g of additionalproduct. Total product obtained 1.95 g; 1H NMR (300 MHz, CDCl₃) δ 7.64(s, 1H), 3.30 (s, 3H), 3.11 (s, 3H), 1.53 (s, 6H). ESMS (M+1)=241.14.

A-12. 2-Chloro-4,5,7,7,8-pentamethyl-7,8-dihydropteridin-6(5H)-one

Sodium hydride (60% oil dispersion; 9 mg, 0.22 mmol) was addedportionwise to a cooled (0° C.) solution of A-11.2-Chloro-4,7,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one (45 mg, 0.187mmol) and iodomethane (14 μL, 0.22 mmol) in DMF (2 ml). The mixture wasstirred for 1 hour then warmed to room temperature overnight. Thereaction was quenched with the addition of water and extracted withethyl acetate (10 mL). The extract was dried over sodium sulfate,filtered, and evaporated in vacuo to give the desired product. 1H NMR(300 MHz, CDCl₃) δ 3.27 (d, J=1.3 Hz, 3H), 3.05 (d, J=1.2 Hz, 3H), 2.42(d, J=2.0 Hz, 3H), 1.34 (d, J=1.2 Hz, 6H).

A-13. 2-Chloro-7,7-dimethyl-7,8-dihydropteridin-6(5H)-one Step 1: Methyl2-[(2-chloro-5-nitro-pyrimidin-4-yl)amino]-2-methyl-propanoate

A solution of 2,4-dichloro-5-nitro-pyrimidine (4.61 g, 23.8 mmol) in THF(50 mL) was cooled to −78° C. Methyl 2-amino-2-methyl-propanoatehydrochloride (3.650 g, 23.8 mmol) was added to the cooled solutionfollowed by the addition of diisopropylethylamine (8.3 mL, 47.5 mmol).The reaction was stirred for 30 minutes then allowed to warm to roomtemperature. Water (100 ml) was added to the reaction and extracted withethyl acetate (3×50 ml), The combined extracts were dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to afford the crudeproduct. The crude product was purified by column chromatography (SiO₂)eluting with ethyl acetate/hexanes to afford the title product, wt. 4.96g that was used in step 2.

Step 2: 2-Chloro-7,7-dimethyl-7,8-dihydropteridin-6(5H)-one

Iron powder (4 g, 14.4 mmol) was added to a solution of methyl2-[(2-chloro-5-nitro-pyrimidin-4-yl)amino]-2-methyl-propanoate (4.03 g,14.4 mmol) in acetic acid (50 mL) and heated to 100 C for 1.5 hours. Thesolvent was evaporated in vacuo and the residue taken into 100 ml ofsaturated sodium bicarbonate and extracted with dichloromethane (2×100mL). The combined extracts were dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford a residue that was washedwith diethyl ether to provide the title product, wt. 567 mg.

A second extraction was performed with dichloromethane (10% methanol),dried with sodium sulfate, filtered, and evaporated in vacuo to providean additional 1.08 g of product. 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s,1H), 8.50 (s, 1H), 7.48 (s, 1H), 1.34 (s, 3H), 0.95 (s, 3H); ESMS(M+1)=212.82

A-14. 2-Chloro-5,7,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

Sodium hydride (60% oil dispersion; 103 mg, 4.29 mmol) was addedportionwise to a cooled (0° C.) solution of2-chloro-7,7-dimethyl-7,8-dihydropteridin-6(5H)-one, A-13 (320 mg, 1.43mmol) and iodomethane (350 μL, 5.72 mmol) in DMF (5 ml). The reactionwas warmed to room temperature and stirred for 2 hours. The reaction waspoured onto 25 ml of water and extracted with ethyl acetate (3×50 ml).The combined extracts were washed with water (25 ml) and brine (50 ml),dried over sodium sulfate, filtered, and evaporated in vacuo. The crudeproduct was purified by column chromatography (SiO₂) eluting with agradient of 0-80% ethyl acetate in hexanes to afford the desiredproduct, wt. 158 mg; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=5.0 Hz, 1H),3.23 (d, J=10.2 Hz, 3H), 3.04 (s, 3H), 1.49 (s, 6H); ESMS (M+1)=269.14.

A-15. 2-Chloro-5,8-diethyl-7,7-dimethyl-7,8-dihydropteridin-6(5H)-one

Iodoethane (158 μl, 1.98 mmol) was added to a mixture of (A-13)2-Chloro-7,7-dimethyl-7,8-dihydropteridin-6(5H)-one (308 mg, 0.7 mmol)and cesium carbonate (690 mg, 2.12 mmol) in DMF (2 ml) and stirred atroom temperature for 12 hours. The reaction was poured into water (25ml) and extracted with ethyl acetate (3×25 ml). The combined extractswere washed with brine, dried over sodium sulfate, filtered andevaporated in vacuo. The crude product was purified by columnchromatography (SiO₂) eluting with a gradient of 0-80% ethyl acetate inhexanes to afford the desired product, wt. 158 mg; ESMS (M+1)=269.14.

A-16.2′-Chloro-4′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-oneStep 1: Ethyl 1-(methylamino)cyclopropane-1-carboxylate

A 2 M solution of sodium carbonate (15 mL of 2 M, 29.89 mmol) was addedto a mixture of ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.65g, 9.963 mmol) in THE followed by the addition of di-tert-butyldicarbonate (3.3 g, 14.94 mmol). The reaction was stirred for 16 hoursat room temperature. Diethyl ether (50 mL) was added to the reaction andthe aqueous layer separated. The organic layer was washed with 1N HCl(10 mL), water (10 mL) and brine, dried over MgSO₄, filtered, andevaporated in vacuo to afford a clear oil. The clear oil was dissolvedin THF and cooled to 0° C. Sodium hydride (1.2 g, 49.82 mmol) was addedin portions wise. After 30 minutes, iodomethane (1.9 mL, 30 mmol) wasadded and the reaction was warmed to room temperature. A solution ofsaturated ammonium chloride (20 mL) was added and the reaction extractedwith diethyl ether (3×20 mL). The combined organic extracts were washedwith brine, dried over MgSO₄, and concentrated to give ethyl1-((tert-butoxycarbonyl)(methyl)amino)cyclopropane-1-carboxylate as aclear liquid, wt. 3.7 g. 1H NMR (400 MHz, CDCl₃) δ 4.21-4.13 (m, 2H),2.90-2.84 (m, 3H), 1.53-1.48 (m, 9H), 1.46 (d, J=8.0 Hz, 5H), 1.26 (d,J=7.0 Hz, 2H).

To ethyl 1-(tert-butoxycarbonyl(methyl)amino)cyclopropanecarboxylate(3.7 g, 15.21 mmol) in dichloromethane (10 mL) was added TFA (8 mL,99.63 mmol). After 1 h, the reaction was concentrated to give thedesired product which was neutralized to provide the title compound as alight yellow oil, wt. 900 mg (63% yield). 1H NMR (300 MHz, CDCl₃) δ 4.16(q, J=7.1 Hz, 2H), 2.46 (s, 3H), 1.97 (s, 1H), 1.32-1.22 (m, 5H), 0.99(dq, J=7.5, 3.9 Hz, 2H). ESMS (M+1)=144.22.

Step 2: Ethyl1-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)cyclopropane-1-carboxylate

A solution of ethyl 1-(methylamino)cyclopropane-1-carboxylate (0.87 g,6.1 mmol) in THF was added to a cooled (0° C.) mixture of2,4-dichloro-6-methyl-5-nitro-pyrimidine (1.264 g, 6.1 mmol) andN,N-diisopropylethylamine (1.3 mL, 7.291 mmol) in tetrahydrofuran (12mL) and stirred for 1 hour. The reaction was quenched with aq. NH₄Cl (5mL) and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo afford thecrude product as a red liquid. The crude was purified by columnchromatography (SiO₂) eluting with a gradient of 0-30% ethyl acetate inhexane in to give the desired product, wt 468 mg (24.5% yield); ESMS(M+1)=315.43.

Step 3:2′-Chloro-4′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

A mixture of ethyl1-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)cyclopropane-1-carboxylate(570 mg, 1.8 mmol) and Fe (607.0 mg, 10.87 mmol) in acetic acid (5.700mL) were refluxed for 1 hour. The solvent was removed in vacuo and 1NHCl (10 ML) was added. The yellow precipitate was filtered off and thefiltrate neutralized with potassium carbonate to pH 10, then extractedwith ethyl acetate (3×10 mL) and dichloromethane/methanol (20/1 ratio,3×10 mL). The combined organic layers were dried over MgSO₄, filtered,and concentrated to give the title product as a white solid (310 mg); 1HNMR (300 MHz, Methanol-d4) δ 3.03 (s, 3H), 2.37 (s, 3H), 1.77-1.41 (m,4H). ESMS (M+1)=239.46.

A-17.2′-Chloro-4′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-pteridin]-6′-oneStep 1: 1-[tert-Butoxycarbonyl(methyl)amino] cyclobutane carboxylic acid

Sodium hydride (60% w/w oil dispersion, 1.200 g, 30.00 mmol) was addedto a cooled (0° C.) solution of1-(tert-butoxycarbonylamino)cyclobutane-1-carboxylic acid (2.153 g,10.00 mmol) in THE (100 mL). After 15 min stirring, iodomethane (7.296g, 3.200 mL, 51.40 mmol) was added. The mixture was allowed to reachroom temperature and stirred overnight. Ethyl acetate (100 mL) and water(100 mL) were added. After 10 min stirring, solvents were evaporatedunder reduced pressure and replaced with diethyl ether which was washedwith saturated sodium bicarbonate (3×50 ml). The combined aqueous layerwas adjusted to pH 3 with 1 N potassium hydrogen sulfate and extractedwith ethyl acetate. The organic layer was washed with brine, dried oversodium sulfate and evaporated in vacuo to provide the title product as ayellow solid (1.4 g, quantitative yield). ¹H NMR (300 MHz, Methanol-d4)δ 7.52-7.21 (m, 5H), 5.12 (d, J=4.1 Hz, 2H), 4.67 (dq, J=24.5, 7.4 Hz,1H), 1.41 (d, J=7.3 Hz, 3H).

Step 2: Methyl1-(tert-butoxycarbonyl(methyl)amino)cyclobutanecarboxylate

1-[tert-butoxycarbonyl(methyl)amino]cyclobutanecarboxylic acid (2.293 g,10 mmol) in benzene (15 mL) and MeOH (5 mL) (3:1 ratio) were addeddropwise to a solution of (trimethylsilyl)diazomethane (6.000 mL of 2 M,12.00 mmol) in diethyl ether. After 1 hour, the reaction was evaporatedin vacuo to provide methyl1-[tert-butoxycarbonyl(methyl)amino]cyclobutanecarboxylate (quantitativeyield) as a light yellow liquid. ¹H NMR (300 MHz, CDCl₃) δ 3.65 (s, 3H),2.74 (d, J=10.6 Hz, 3H), 2.38 (t, J=10.2 Hz, 2H), 2.34-2.20 (m, 2H),2.00 (p, J=9.2 Hz, 1H), 1.71 (tq, J=10.0, 6.8, 5.0 Hz, 1H), 1.30 (s,9H).

Step 3: Methyl 1-(methylamino)cyclobutane carboxylate hydrochloride

Methyl 1-[tert-butoxycarbonyl(methyl)amino]cyclobutanecarboxylate (2.433g, 10 mmol) in dioxane was added HCl (20 mL of 4 M, 80.00 mmol) indioxane. After stirring for 2 h, no more SM showed in LCMS and thesolution was concentrated to dryness. The residue was triturated withdiethyl ether (2×10 mL) to provide the desired product as yellow stickygum, which was used in the next step. ESMS (M+1)=144.06.

Step 4: Methyl1-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-methylamino]cyclobutanecarboxylate

At 0° C., a cooled solution of K₂CO₃ (1.32 g, 9.205 mmol) in ice water(10 mL) was added to 2,4-dichloro-6-methyl-5-nitro-pyrimidine and methyl1-(methylamino)cyclobutanecarboxylate hydrochloride (661.5 mg, 3.682mmol) in acetone (20 mL) and stirred for 1 hour at 0° C. The reactionwas quenched with saturated NH₄Cl (5 mL) and extracted with diethylether. extracts were evaporated in vacuo to provide the desired productas a red liquid. Purification by silica gel chromatography (0-30%EtOAc/Hexane for 30 minutes) provided desired product, methyl1-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-methylamino]cyclobutanecarboxylate,as yellow sticky liquid (206 mg, 17.5% yield. major isomer with lowerR_(f)). ¹H NMR (300 MHz, CDCl₃) δ 3.71 (s, 3H), 2.81 (s, 3H), 2.65 (ddd,J=13.5, 5.8, 3.7 Hz, 2H), 2.41 (s, 3H), 2.39-2.24 (m, 2H), 2.24-2.06 (m,1H), 1.92-1.71 (m, 1H). ESMS (M+1)=315.12.

Step 5: 2-Chloro-4,8-dimethyl-spiro[5H-pteridine-7,1′-cyclobutane]-6-one

Methyl1-[(2-chloro-6-methyl-5-nitro-pyrimidin-4-yl)-methylamino]cyclobutanecarboxylate(200 mg, 0.6355 mmol), Zn (210.2 mg, 3.214 mmol) and NH₄Cl (354 mg,6.618 mmol) in anhydrous methanol was heated to reflux. After 1 h, notmuch product formed. The reflux was kept overnight. The reaction went tocompletion and cooled down to RT. Dichloromethane (20 mL) was added. Thecloudy solution was filtered and concentrated. The crude product waspurified by column chromatography (SiO₂) eluting with 0-10% MeOH indichloromethane to give the desired product,2-chloro-4,8-dimethyl-spiro[5H-pteridine-7,1′-cyclobutane]-6-one (62 mg,0.2442 mmol, 38% yield) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ3.27 (d, J=1.8 Hz, 3H), 2.82-2.46 (m, 4H), 2.31 (d, J=1.8 Hz, 3H), 2.06(dddd, J=17.5, 9.3, 3.3, 1.6 Hz, 1H), 1.91 (dqd, J=10.3, 5.2, 2.6 Hz,1H). ESMS (M+1)=253.14

A-18(7S)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-oneStep 1: (7S)-2-Chloro-7-ethyl-7,8-dihydropteridin-6(5H)-one

2,4-Dichloropyrimidin-5-amine (5.4 g, 32.92 mmol), (R)-2-aminobutanoicacid (4.07 g, 39.5 mmol), and diisopropylethylamine (23 ml, 131.7 mmol)was taken into n-butanol (80 ml) and water (40 ml) and heated to 128 Cfor 24 hours. The solvent was evaporated in vacuo. To the residue wasadded 100 ml of water and extracted with ethyl acetate (3×80 ml). Theextracts were combined, dried over sodium sulfate, filtered, andevaporated in vacuo to afford the product that was triturated withisopropanol to provide a solid that was collected by vacuum filtrationand dried to provide 2.46 g of the product. The filtrate was evaporatedin vacuo to give additional crude product. This was purified by columnchromatography (SiO₂) eluting a gradient of 0-100% ethyl acetate inhexanes to provide 1.46 g of additional product. Total product obtained.3.92 g. 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.46 (s, 1H), 7.51(s, 1H), 4.21 (td, J=4.8, 1.7 Hz, 1H), 1.77 (dddd, J=44.2, 13.9, 7.2,5.1 Hz, 2H), 0.86 (t, J=7.4 Hz, 3H); ESMS (M+1)-213.12.

Step 2: (7S)-2-Chloro-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one

To a mixture of (7S)-2-chloro-7-ethyl-7,8-dihydropteridin-6(5H)-one(1.46 g, 6.65 mmol) and potassium carbonate (2.02 g, 14.6 mmol) in 20 mlof acetone was added iodomethane (0.5 ml, 8 mmol). The reaction wasstirred at room temperature for 2 days. The solvent was evaporated invacuo and the residue was taken into water and stirred. The precipitatewas collected by vacuum filtration, washed well with water, and driedunder vacuum to provide the title product, wt. 1.41 g (92% yield). 1HNMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.80 (s, 1H), 4.28 (t, J=4.8 Hz,1H), 3.21 (s, 3H), 2.07-1.49 (m, 2H), 0.84 (t, J=7.4 Hz, 3H); ESMS(M+1)=227.09.

Step 3:(7S)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-Chloro-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (205 mg,0.9 mmol) was taken into 2 ml of DMF. Sodium hydride (60% oildispersion; 72 mg, 1.8 mmol) was added to the solution followed by theaddition of 2-iodopropane (180 μl, 1.8 mmol). After 1 hour, 0.2 ml ofmethanol was added to the reaction then evaporated in vacuo. The crudewas purified by column chromatography (SiO₂) eluting with 0-100% ethylacetate in hexanes to afford 157 mg of the desired product. 1H NMR (400MHz, DMSO-d6) δ 7.87 (s, 1H), 4.49-4.26 (m, 2H), 3.24 (s, 3H), 1.92-1.59(m, 2H), 1.33 (d, J=6.8 Hz 6H) 0.74 t, J=75H, 3H); ESMS (M+1)=269.46.

A-19(7S)-2-Chloro-5-ethyl-8-isopropyl-7-methyl-7,8-dihydropteridin-6(5H)-oneStep 1: (7S)-2-Chloro-7-methyl-7,8-dihydropteridine-6(5H)-one

The compound was prepared by reaction of 2,4-Dichloropyrimidin-5-amine(11 g, 67 mmol) and (2S)-2-aminopropanoic acid (7.17 g, 80.5 mmol) viathe procedure reported for A-18, Step 1 to provide the desired product,wt. 9.7 g (72% yield); ESMS (M+1)=199.03

Step 2: (7S)-2-Chloro-5-ethyl-7-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-chloro-7-methyl-7,8-dihydropteridine-6(5H)-one and iodoethane viaprocedure reported for A-18, Step 2 to provide the desired product, wt.3.31 g (74% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.89 (s,1H), 4.30 (q, J=6.8 Hz, 1H), 3.84 (ddd, J=14.1, 7.0, 2.2 Hz, 2H), 3.32(s, 1H), 1.36 (d, J=6.8 Hz, 3H), 1.09 (t, J=7.1 Hz, 3H); ESMS(M+1)=227.13.

Step 3:(7S)-2-Chloro-5-ethyl-8-isopropyl-7-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared via the same procedure found for A-18, Step 3to provide the desired product, wt. 515 mg (52% yield); 1H NMR (400 MHz,DMSO-d6) δ 8.57 (s, 1H), 7.89 (s, 1H), 4.30 (q, J=6.8 Hz, 1H), 3.84(ddd, J=14.1, 7.0, 2.2 Hz, 2H), 3.32 (s, 1H), 1.36 (d, J=6.8 Hz, 3H),1.09 (t, J=7.1 Hz, 3H); ESMS (M+1)=269.14.

A-20.(S)-2-Chloro-7-((R)-1-methoxyethyl)-5,8-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1:(7S)-2-Chloro-7-((R)-1-methoxyethyl)-7,8-dihydropteridin-6(5H)-one

(2S,3R)-2-Amino-3-methoxy-butanoic acid (1 g, 7.5 mmol),2,4-dichloropyrimidin-5-amine (1000 mg, 6.1 mmol), andN,N-diisopropylethylamine (3.2 mL, 18.23 mmol) was taken into ethanol(15 mL) and heated at 100° C. for 16 hours. The reaction was cooled toroom temperature. A precipitate formed upon cooling. The precipitate wascollected by vacuum filtration, washed with hexanes, and dried toprovide the desired product (800 mg, 54%); ESMS (M+1)=243.12.

Step 2:(7S)-2-Chloro-7-((R)-1-methoxyethyl)-5,8-dimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-Chloro-7-((R)-1-methoxyethyl)-7,8-dihydropteridin-6(5H)-one (0.75g, 3.09 mmol) and cesium carbonate (3.02 g, 9.27 mmol), and iodomethane(470 μl, 7.42 mmol) was taken into DMF (5 ml) and stirred for 2 hours.Water was added to the reaction mixture and extracted with ethyl acetate(3×50 ml). The combined extracts were washed with water and brine, driedover anhydrous sodium sulfate, filtered, and evaporated in vacuo toafford the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (d, J=21.5Hz, 1H), 4.39 (dd, J=14.6, 2.7 Hz, 1H), 3.81-3.61 (m, 1H), 3.34 (s, 3H),3.23 (d, J=7.9 Hz, 3H), 3.12 (dd, J=13.8, 10.2 Hz, 6H), 1.12 (dd,J=22.7, 6.5 Hz, 3H); ESMS (M+1)=271.12

A-21. (7S)-2-Chloro-7-methyl-7,8-dihydropteridin-6(5H)-one

2,4-Dichloropyrimidin-5-amine (11 g, 67.08 mmol), (2S)-2-aminopropanoicacid (7.172 g, 80.5 mmol) and N,N-diisopropylethylamine (46 mL, 268mmol) in ethanol (100 mL) was heated at 128° C. for 14 h. The reactionwas evaporated in vacuo to half volume. Water (100 ml) was added to themixture at room temperature and stirred for 1 hour. The resultingprecipitate was collected by vacuum filtration, washed well with waterand dried to provide the desired product wt. 9.56 g; Analytical SFC(column: cellulose 2 (40% ethanol, 60% CO₂, isocratic): Rt 0.983 mins.)showed a S:R mixture 2:1; ESMS (M+1)=199.03.

A-22. (7S)-2-Chloro-5,8-diethyl-7-methyl-7,8-dihydropteridin-6(5H)-one

Iodoethane (650 μL, 8.04 mmol) was added to a mixture of(7S)-2-chloro-7-methyl-7,8-dihydro-5H-pteridin-6-one (577 mg, 2.87 mmol)and cesium carbonate (2.81 g, 8.6 mmol) in DMF (5 ml) and stirred atroom temperature for 12 hours. The reaction was evaporated in vacuo togive a solid residue. Water (50 ml) was added to the residue andextracted with ethyl acetate (3×50 ml). The combined extracts werewashed with brine, dried over sodium sulfate, filtered, and evaporatedin vacuo to afford the crude product. The crude was purified by columnchromatography (SiO₂) eluting with a gradient of 10% ethyl acetate inhexanes too 100% ethyl acetate. Evaporation of the desired fractionsafforded the desired product, wt. 581 mg; ESMS (M+1)=255.14.

A-23. (7S)-2-Chloro-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one

To a (7S)-2-chloro-7-methyl-7,8-dihydropteridin-6(5H)-one (4.37 g, 21.76mmol) in acetone (63.97 mL) was added potassium carbonate (6.616 g,47.87 mmol) and iodomethane (1.625 mL, 26.1 mmol) and the reaction wasstirred at room temperature for 2 days. The reaction was evaporated invacuo to provide a solid residue. Water (6 ml) was added to the solid,filtered, and washed with water (2×) and dried to provide the desiredproduct: wt. 4.0519 g; The analytical SFC (column: cellulose 2 (40%ethanol, 60% CO₂, isocratic): Rt 0.927 mins.) shows the S:R ratioremains 2:1; 1H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.81 (s, 1H),4.32 (q, J=6.7 Hz, 1H), 3.20 (s, 3H), 1.37 (d, J=6.8 Hz, 3H); ESMS(M+1)=203.13.

A-24. (7S)-2-Chloro-8-ethyl-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one

Iodoethane (400 μL, 4.911 mmol) was added to a mixture of(7S)-2-Chloro-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one and cesiumcarbonate (2.1 g; 6.55 mmol) in 5 ml of DMF (6 mL) and stirred 50° C.for 1 hour. The reaction was evaporated in vacuo to afford a solidresidue. Water (30 ml) was added and the solution was extracted withethyl acetate (3×30 ml). The combined extracts were washed with brine,dried over sodium, sulfate, filtered, and evaporated to afford gum thatwas triturated with ether/hexane to provide the desired product as asolid, wt. 0.7 g. The analytical SFC (column: cellulose 2 (40% ethanol,60% CO₂, isocratic): Rt 0.74 mins.) demonstrates the S:R ratio is 3:2;ESMS (M+1)=241.09.

A-25. (7S)-2-chloro-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one

2,4-Dichloropyrimidin-5-amine (5 g, 30.5 mmol),(2S)-2-amino-4-hydroxy-butanoic acid (5 g, 42 mmol) anddiisopropylethylamine (16 mL, 91.5 mmol) were taken into ethanol (10 mL)and heated to 120° C. for 22 hours. The reaction was cooled to roomtemperature and a precipitate formed. The precipitate was collected byvacuum filtration, washed with ethanol, and dried to provide the desiredproduct, wt. 4.76 g (68.% yield); ESMS (M+1)=229.07; Chiral HPLC(ChiralPAK IC column; 50%/MeOH/50% Ethanol): Rt 6.625 mins., 81% ee.

A-26.(7S)-2-Chloro-5,8-diethyl-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one

Iodoethane (1.5 ml, 19.25 mmol) was added to a mixture of(7S)-2-chloro-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one (2 g,8.75 mmol) and cesium carbonate (8.55 g, 26.24 mmol) in DMF (25 mL). Thereaction was stirred for 20 hours at room temperature. Water (10 ml) wasadded to the reaction followed by extraction with ethyl acetate (3×25mL). The combined extracts were washed with brine (1×20 mL) and water(2×20 mL), dried over sodium sulfate, filtered, and concentrated todryness to afford the desired product, ESMS (M+1)=285.13.

A-27. (7R)-2-Chloro-7-ethyl-7-methyl-7,8-dihydropteridin-6(5H)-one

2,4-Dichloropyrimidin-5-amine (8.677 g, 52.9 mmol),(2R)-2-amino-2-methylbutanoic acid (6.198 g, 52.9 mmol) andN,N-diisopropylethylamine (36.86 mL, 212 mmol) were taken into ethanol(100 mL) and heated at 128° C. for 14 hours. The reaction mixture wasevaporated in vacuo to half volume followed by the addition of 100 ml ofwater and stirred at room temperature for 1 hour. The resultingprecipitate was collected by vacuum filtration and washed with water.The crude was stirred in isopropanol and filtered to remove theinsoluble starting material. The filtrates were concentrated in vacuo,stirred in dichloromethane, and filtered to provide the desired product,wt. 1.71 g; 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.47 (s, 1H),7.51 (s, 1H), 1.88 (dd, J=13.8, 7.3 Hz, 1H), 1.53 (dd, J=13.9, 7.3 Hz,1H), 1.38 (s, 3H), 0.82 (t, J=7.3 Hz, 3H); ESMS (M+1)=227.13.

A-28.(7R)-2-Chloro-5,7,8-triethyl-7-methyl-7,8-dihydropteridin-6(5H)-one

Iodoethane (363 uL, 4.54 mmol) was added to a mixture of(7R)-2-chloro-7-ethyl-7-methyl-5,8-dihydropteridin-6-one (368 mg, 1.6mmol) and cesium carbonate (1.59 g, 4.87 mmol) in DMF (2.7 mL) andstirred at room temperature for 12 hours. The reaction was evaporated invacuo to provide a residue. Water (50 ml) was added and extracted withethyl acetate (3×50 ml). The combined ethyl acetate extracts were washedwith brine, dried over sodium sulfate, filtered, and evaporated in vacuoto provide the crude product. The crude product was purified by columnchromatography eluting with a gradient of 10-100% ethyl acetate inhexanes to provide the desired product, wt. 386 mg; ESMS (M+1)=283.55.

A-29. (7S)-2-Chloro-7-ethyl-7/methyl-7,8-dihydropteridin-6-one

The compound was prepared by reaction of 2,4-dichloropyrimidin-5-amineand (2S)-2-amino-2-methylbutanoic acid via the procedure reported forA-27 to provide 5.43 g of the desired product; 1H NMR (400 MHz, DMSO-d6)δ 10.68 (s, 1H), 8.47 (s, 1H), 7.51 (s, 1H), 1.88 (dd, J=13.8, 7.3 Hz,1H), 1.53 (dq, J=14.6, 7.3 Hz, 1H), 1.38 (s, 3H), 0.83 (t, J=7.3 Hz,3H); ESMS (M+1)=227.09.

A-30.(7S)-2-Chloro-5,7,8-triethyl-7-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediate A-29 andiodoethane via the procedure reported for A-28 to provide 643 mg of thedesired product; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (s, 1H), 3.98 (dd,J=14.1, 7.1 Hz, 1H), 3.80 (dd, J=14.1, 7.0 Hz, 1H), 3.68 (dd, J=14.1,7.0 Hz, 1H), 3.41 (dt, J=14.1, 6.9 Hz, 1H), 1.89 (dq, J=14.5, 7.2 Hz,2H), 1.59 (s, 3H), 1.14 (dt, J=27.7, 7.0 Hz 6H), 0.68 (t, J=7.4 Hz, 3H);ESMS (M+1)=283.19.

A-31.(7S)-2-Chloro-7-ethyl-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of compound A-29 and iodomethanevia the procedure reported for A-28 to provide the desired product, 246mg (66% yield); ESMS (M+1)=255.14.

A-32.(7R)-2-Chloro-7-ethyl-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of compound A-27 and iodomethanevia the procedure reported for A-28 to provide the desired product, 263mg (70% yield); ESMS (M+1)=255.14.

A-33.2′-Chloro-4′,5′,8′-trimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

Sodium hydride (40.00 mg, 1.000 mmol) was added to a cooled (0° C.)solution of2-chloro-4,8-dimethyl-spiro[5H-pteridine-7,1′-cyclopropane]-6-one, A-16(120 mg, 0.5 mmol) and iodomethane (50 μL, 0.7500 mmol) in DMF (10 ml)The mixture was stirred for 1 hour, then warmed to room temperature andstirred for 16 hours. The reaction was quenched with saturated NH4Cl,then poured into a saturated NaHCO₃ solution, and extracted with ethylacetate. The extract was dried over MgSO₄, filtered, and evaporated togive desired product, wt. 54 mg (40% yield). 1H NMR (300 MHz, CDCl₃) δ3.27 (s, 3H), 2.87 (s, 3H), 2.43 (s, 3H), 1.39-1.30 (m, 2H), 1.16-1.09(m, 2H). ESMS (M+1)=253.46.

A-34.(7S)-2-Chloro-4-isopropyl-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

(2S)-2-(Methylamino)propanoic acid (500.3 mg, 4.852 mmol),2,4-dichloro-6-isopropylpyrimidin-5-amine (500 mg, 2.426 mmol), andsodium bicarbonate (713.3 mg, 8.491 mmol) were taken into 95% ethanoland heated to 90° C. for 16 hours. Water was added to the reactionmixture followed by extraction with ethyl acetate (3×150 ml). Thecombined extracts were washed with water and brine, dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to provide the crudeproduct. The crude product was purified by prep C18 column (10-100%acetonitrile in water (0.1% TFA)). The desired fractions were combinedand evaporated in vacuo to provide the title product, wt. 500 mg (81%yield). 1H NMR (300 MHz, CDCl₃) δ 8.49 (s, 1H), 4.20 (q, J=6.9 Hz, 1H),3.15 (s, 3H), 2.97 (p, J=6.7 Hz, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.29 (dd,J=11.1, 6.7 Hz, 6H); ESMS (M+1) 253.07.

A-35. (7S)-2-Chloro-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-Chloro-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one, (Compound A-1;9.1 g, 40.15 mmol) and potassium carbonate (8.32 g, 60.22 mmol) weretaken into DMF (100 ml) and cooled to 0° C. Iodomethane (3 ml, 48.18mmol) was added to the cooled solution and stirred overnight. Thereaction was poured into water (200 ml) and extracted with ethyl acetate(3×150 ml). The combined extracts were washed with 150 ml of water andbrine (200 ml) then dried over anhydrous sodium sulfate, filtered, andevaporated in vacuo to afford the crude product. The crude was purifiedby column chromatography (SiO₂) eluting with 5-80% ethylacetate/hexanes. The desired fractions were evaporated to afford thedesired product as a white solid (6 g; 62% yield). ¹H NMR (300 MHz,CDCl₃) δ 7.60 (s, 1H), 4.17 (q, J=6.9 Hz, 1H), 3.26 (s, 3H), 3.07 (s,3H), 1.38 (d, J=6.9 Hz, 3H). [α]_(D)=24.1° (chloroform; c=1).

A-36.2′-Chloro-5′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by the same method as described in A-16 andA-33 to provide the title product. 1H 1H NMR (300 MHz, CDCl₃) δ 7.53 (s,1H), 3.22 (s, 3H), 2.82 (s, 3H), 1.46 (dd, J=8.1, 5.4 Hz, 2H), 1.24 (dt,J=9.5, 4.5 Hz, 2H). ESMS (M+1)=239.11.

A-37.2′-Chloro-5′,8′-diethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-oneStep 1: Ethyl1-((2-chloro-5-nitropyrimidin-4-yl)amino)cyclopropane-1-carboxylate

The compound was prepared in a similar manner as intermediate A-16 bythe reaction of 2,4-dichloromethane-5-nitropyrimidine and ethyl1-aminocyclopropane-1-carboxylate to provide the title compound as ayellow solid; wt. 1.23 g (99% yield); ESMS (M+1)=286.97.

Step 2:2′-Chloro-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one(A-53)

The compound was prepared in a similar fashion as Intermediate A-13,Step 2 to provide the title compound, wt. 1.72 g. 1H NMR (400 MHz,DMSO-d6) δ 10.68 (s, 1H), 8.50 (s, 1H), 7.48 (s, 1H), 1.34 (s, 2H), 0.95(s, 2H).

Step 3:2′-Chloro-5′,8′-diethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

Iodoethane (600 μl, 7.3 mmol) was added to a mixture of2′-chloro-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one(575 mg, 2.61 mmol) and cesium carbonate (2.55 g, 7.84 mmol) in DMF (4ml) and heated to 50° C. for 2 hours. Water (50 ml) was added to thereaction and extracted with ethyl acetate (3×50 ml). The combinedextracts were washed with brine, dried over sodium sulfate, filtered,and evaporated in vacuo to afford the crude product. The crude productwas purified by column chromatography (SiO₂) eluting with a gradient of0-30% ethyl acetate in hexane. The desired fractions were evaporated invacuo to afford the title compound, 192 mg (27% yield). 1H NMR (300 MHz,CDCl₃) δ 7.58 (s, 1H), 3.85 (q, J=7.1 Hz, 2H), 3.30 (q, J=7.0 Hz, 2H),1.53 (dd, J=7.8, 5.6 Hz, 2H), 1.26-1.06 (m, 8H); ESMS (M+1)=267.48.

A-38.(7S)-2-chloro-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-oneStep 1: N-((benzyloxy)carbonyl)-N-(methyl-d3)-L-alanine

At 0° C., NaH (537.5 mg, 13.44 mmol) was added to a solution of(2S)-2-(benzyloxycarbonylamino)propanoic acid (1 g, 4.480 mmol) in THF(100 mL). After stirring for 15 minutes, trideuterio(iodo)methane (3.6g, 24.83 mmol) was added and mixture was warmed to room temperature andstirred overnight. Ethyl acetate (100 mL) and water (100 mL) were added.After 10 min stirring, solvents were evaporated under reduced pressureand replaced with diethyl ether. The solution was washed with saturatedNaHCO₃ several times. The combined aqueous layer was adjusted to pH=3with aqueous 1N KHSO₄ solution and extracted with ethyl acetate. Theorganic layer was washed with brine and dried over Na₂SO₄. Evaporationof the solvent gave product 1,(2S)-2-[benzyloxycarbonyl(trideuteriomethyl)amino]-propanoic acid asyellow oil (1.1 g, quantitative yield). 1H NMR (300 MHz, Methanol-d4) δ7.52-7.21 (m, 5H), 5.12 (d, J=4.1 Hz, 2H), 4.67 (dq, J=24.5, 7.4 Hz,1H), 1.41 (d, J=7.3 Hz, 3H).

Step 2

(methyl-d3)-L-alanine(2S)-2-[benzyloxycarbonyl(trideuteriomethyl)amino]propanoicacid 1 (1.1 g, 4.578 mmol) in methanol was added to 10% Pd/C (487.2 mg,0.4578 mmol). The mixture was hydrogenated under hydrogen (50 Psi) for20 hours. The reaction mixture was filtered through MeOH-washedFlorisil. The filtrate was evaporated in vacuo and dried to give thetitle product as a white solid (477 mg, 98% yield), 1H NMR (400 MHz,DMSO-d6) δ 3.09 (q, J=6.9 Hz, 1H), 1.22 (d, J=7.1 Hz, 3H).

Step 3:(S)-2-chloro-4,7-dimethyl-8-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

(2S)-2-(trideuteriomethylamino)propanoic acid 2 (477 mg, 4.494 mmol),2,4-dichloro-6-methyl-pyrimidin-5-amine (640.0 mg, 3.595 mmol) andsodium bicarbonate (1.087 g, 12.94 mmol) were taken into EtOH (9.5 mL)and water (0.5 mL) and refluxed overnight. The reaction was neutralizedwith 6N HCl neutralize the solution to pH 6 then extracted withdichloromethane (30 mL). The aqueous layer was separated and extractedwith dichloromethane twice (2×10 mL). The combined organic extracts werewashed with water and concentrated to give pink solid. Dichloromethane(10 mL) was added to the solid and centrifuged to separate solid. Thestep was repeated once more and the resulting white solid was cleanproduct. The combined dichloromethane layers was purified by columnchromatography (SiO₂; 40 g) eluting with a gradient of 10-40% methanolin dichloromethane to give more product 3,(7S)-2-chloro-4,7-dimethyl-8-(trideuteriomethyl)-5,7-dihydropteridin-6-one,as white solid (402 mg, 48.7% yield). 1H NMR (300 MHz, CD₃OD) δ 4.15 (d,J=4.0 Hz, 1H), 2.33 (s, 3H), 1.46 (d, J=6.9 Hz, 3H).

A-39.(7S)-2-chloro-4,8-dimethyl-7-(methyl-d3)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by the procedure described in A-2 via reactionof methyl N-methyl-L-alanine-3,3,3-d3 and2,4-dichloro-6-methylpyrimidin-5-amine to provide the title product. 83%yield; ESMS (M+1)=231.07

A-40. MethylN-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate

A solution of 2,4-Dichloro-6-methyl-5-nitro-pyrimidine (1.86 g, 8.96mmol) in 20 ml of acetone was added dropwise to a mixture of methyl(2S)-2-(methylamino)propanoate (1 g, 8.54 mmol) and potassium carbonate(1.77 g, 12.8 mmol) in acetone and water. The reaction was stirred atroom temperature for 16 hours. The mixture was evaporated in vacuo andthe residue was taken into a water and extracted with ethyl acetate(3×75 ml). The combined extracts were combined, washed with brine, driedover sodium sulfate, filtered, and evaporated in vacuo to afford thetitle product as a viscous yellow oil, wt. 1.54 g (62.5% yield). 1H NMR(300 MHz, CDCl₃) δ 5.34 (q, J=7.3 Hz, 1H), 3.78 (s, 3H), 2.88 (s, 3H),2.48 (s, 3H), 1.57 (d, J=7.3 Hz, 3H).

A-41. (7S)-2-Chloro-7-ethyl-8-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of (2S)-2-(methylamino)butanoicacid trifluoroacetate salt and 2,4-dichloro-6-methyl-pyrimidin-5-aminefollowing the procedure reported for intermediate A-8 to provide thetitle product as a white solid, 89% yield. 1H NMR (300 MHz, Methanol-d4)δ 7.55 (s, 1H), 4.34 (dd, J=5.5, 3.5 Hz, 1H), 3.16 (s, 3H), 2.04 (dtdd,J=12.3, 9.0, 6.5, 2.7 Hz, 2H), 0.89 (t, J=7.5 Hz, 3H).

A-42. (7S)-2-Chloro-7-ethyl-5,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of Intermediate A-41 andiodomethane following the same procedure reported for intermediate A-35to provide the title product as yellow crystalline solid. 1H NMR (300MHz, CDCl₃) δ 7.65 (s, 1H), 4.26 (dd, J=5.9, 3.5 Hz, 1H), 3.35 (s, 3H),3.16 (s, 3H), 2.16-1.77 (m, 2H), 0.84 (t, J=7.5 Hz, 3H).

A-43. (7S)-2-Chloro-5,7-diethyl-8-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of Intermediate A-41 andiodoethane following the same procedure reported for intermediate A-35to provide the title product. 1H NMR (300 MHz, CDCl₃) δ 7.66 (s, 1H),4.23 (dd, J=5.9, 3.5 Hz, 1H), 4.06 (dq, J=14.3, 7.2 Hz, 1H), 3.85 (dq,J=14.2, 7.1 Hz, 1H), 3.49 (q, J=7.0 Hz, OH), 3.15 (s, 3H), 2.04 (dtd,J=15.0, 7.5, 3.6 Hz, 1H), 1.89 (dtd, J=14.5, 7.4, 5.8 Hz, 1H), 1.26 (q,J=7.3 Hz, 4H), 0.83 (t, J=7.5 Hz, 3H).

A44. (7S)-2-Chloro-8-ethyl-4,7-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1. MethylN-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-ethyl-L-alaninate

The compound was prepared by reaction of2,4-dichloro-6-methyl-5-nitro-pyrimidine and methyl(2S)-2-(ethylamino)propanoate in the same manner as A-40 to provide thetitle product, wt. 1.24 g (61% yield). ESMS (M+1)=303.38.

Step 2. (7S)-2-Chloro-8-ethyl-4,7-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reduction of methylN-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-ethyl-L-alaninate. Thestarting material was dissolved in 40 ml of THF and hydrogenated (50psi) overnight in the presence of platinum (351 mg, 0.054 mmol) andbis[(E)-1-methyl-3-oxo-but-1-enoxy]-oxo-vanadium (70.11 mg, 0.26 mmol).The reaction was filtered and evaporated to provide the title productthat was used without further purification. ESMS (M+1)=241.42.

A-45.(7S)-2-Chloro-7-ethyl-5-methyl-8-(2,2,2-trifluoroethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-chloro-7-ethyl-5-methyl-7,8-dihydropteridin-6-one (IntermediateA-47) and 1,1,1-trifluoro-2-iodo-ethane following the procedure reportedfor A-24 to afford the title product. 1H NMR (300 MHz, CDCl3) δ 7.74 (s,1H), 5.27-5.04 (m, 1H), 4.29 (dt, J=17.2, 8.6 Hz, 1H), 3.55-3.33 (m,1H), 3.31 (d, J=4.2 Hz, 3H), 2.04-1.82 (m, 1H), 1.73 (ddd, J=23.1, 15.2,7.9 Hz, 1H), 0.86-0.73 (m, 3H); ESMS (M+1)=309.08.

A-46. (7S)-2-Chloro-7-ethyl-7,8-dihydropteridin-6(5H)-one

2,4-Dichloropyrimidin-5-amine (15 g, 91.47 mmol), (2S)-2-aminobutanoicacid (11.32 g, 109.8 mmol) and diisopropylethylamine (64 mL, 366 mmol))were taken into ethanol (120 mL) and heated at 128° C. for 14 hours. Thereaction was evaporated to half volume and water (100 ml) was added tothe mixture. A precipitate formed that was collected by vacuumfiltration yielding 6.85 g of the product as a mixture of the S and Renantiomers. The filtrate was concentrated to remove water and aprecipitate began to from, The precipitate was collected by vacuumfiltration, washed well with water to afford 9.16 g of the product asthe S enantiomer. SFC chromatography (SW column; 40 nm×16 nm; 25%methanol in CO₂, isocratic; 2 ml/min). Rt 0.474 mins. (93.5% ee). 1H NMR(400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.46 (s, 1H), 7.51 (s, 1H), 4.21(td, J=4.8, 1.7 Hz, 1H), 1.77 (dddd, J=44.2, 13.9, 7.2, 5.1 Hz, 2H),0.86 (t, J=7.4 Hz, 3H); ESMS (M+1)=213.12.

A-47. (7S)-2-Chloro-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one

To a solution of (7S)-2-Chloro-7-ethyl-7,8-dihydropteridin-6(5H)-one(1.46 g, 6.65 mmol) in acetone (21 ml) was added potassium carbonate(2.02 g, 14.6 mmol) and iodomethane (500 ul, 8 mmol) and the mixture wasstirred at room temperature for 2 days. The reaction was evaporated invacuo to provide a solid residue. Water (10 ml) was added and stirred atroom temperature for 30 minutes. The precipitate was collected by vacuumfiltration and washed well with water. The solid was dried under vacuumat 50° C. to afford the title product, wt. 1.41 g (92% yield). 1H NMR(400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.80 (s, 1H), 4.28 (t, J=4.8 Hz, 1H),3.21 (s, 3H), 2.07-1.49 (m, 2H), 0.84 (t, J=7.4 Hz, 3H). ESMS(M+1)=227.09. SFC chromatography (SW column; 40 nm×16 nm; 25% methanolin CO2, isocratic; 2 ml/min): Rt 0.671 mins. (95% ee).

A-49. (7S)-2-chloro-8-methyl-7-propyl-7,8-dihydropteridin-6(5H)-one

(S)-2-(methylamino)pentanoic acid hydrochloride (613 mg, 3.66 mmol) and2,4-dichloropyrimidin-5-amine (500 mg, 3.05 mmol were taken into ethanol(20 ml) and diisopropylethylamine (2.7 ml, 15.24 mmol) and heated to120° C. for 24 hours. The reaction was cooled room temperature and aprecipitate formed. The precipitate was collected by vacuum filtrationand washed with ethanol. The solid was dried under vacuum at 50° C. toprovide the title product, wt. 420 mg (57% yield); 1H NMR (300 MHz,DMSO-d6) δ 7.45 (s, 1H), 4.18 (d, J=3.5 Hz, 1H), 2.99 (s, 3H), 1.91-1.66(m, 2H), 1.13 (dt, J=14.9, 7.6 Hz, 2H), 0.83 (t, J=7.3 Hz, 3H); ESMS(M+1)=241.09.

A-50. (7S)-2-chloro-5,8-dimethyl-7-propyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-chloro-8-methyl-7-propyl-7,8-dihydropteridin-6(5H)-one, A-49 (200mg, 0.83 mmol), iodomethane (62 ul, 1 mmol), and potassium carbonate(345 mg, 2.5 mmol) were taken into acetone and stirred at roomtemperature for 16 hours. The reaction was evaporated in vacuo toprovide a solid that was taken into water and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the title product, wt. 200mg (96% yield). 1H NMR (300 MHz, CDCl₃) δ 7.65 (s, 1H), 4.25 (dd, J=6.1,3.8 Hz, 1H), 3.34 (s, 3H), 3.15 (s, 3H), 2.04-1.70 (m, 2H), 1.34-1.13(m, 2H), 0.91 (t, J=7.3 Hz, 3H); ESMS (M+1)=255.14.

A-51. 2′-Chloro-5′,8′-dihydro-6′H-spiro[oxetane-3,7′-pteridin]-6′-one

2,4-Dichloropyrimidin-5-amine (235 mg, 1.433 mmol), (2R)-2-aminobutanoicacid (155.6 mg, 1.509 mmol) and DIPEA (779.9 mg, 1.051 mL, 6.034 mmol)was taken into n-BuOH (20 mL) and water (10 mL) and heated at 128° C.for 24 hours. The solvent was evaporated in vacuo. To the residue wasadded water (30 ml) that was extracted with ethyl acetate (2×) anddichloromethane (2×). The combined organic layers were dried over MgSO₄,filtered and evaporated. The crude product was purified by columnchromatography (SiO₂) eluting with 10-100% ethyl acetate in hexanes toprovide the title product (28.1 mg). ESMS (M+1)=227.04.

A-52.2′-Chloro-5′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[oxetane-3,7′-pteridin]-6′-one

To 2-chlorospiro[5,8-dihydropteridine-7,3′-oxetane]-6-one (148 mg,0.6481 mmol) in DMF (2.4 mL) at 0° C. was added Mel (552.0 mg, 242.1 μL,3.889 mmol), followed by the addition of NaH (155.5 mg, 3.889 mmol). Thereaction temperature was raised to room temperature and stirred for 2hours. The solvent was evaporated and water (20 ml) was added to theresidue followed by extraction with dichloromethane (3×). The extractswere combined and dried over sodium sulfate, filtered, and evaporated toafford the crude product. The crude was purified by columnchromatography (SiO₂) eluting with a gradient of 10-100% ethyl acetatein hexanes to provide the title product as a white solid: 1H NMR (300MHz, CDCl₃) δ 7.60 (s, 1H), 5.25 (d, 2H), 4.80 (d, 2H), 3.51 (s, 3H),3.31 (s, 3H). ESMS 255.09 (M+1).

A-53:2′-chloro-4′-methyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

See A-37, Step 2.

A-54: 2-Chloro-5,7,7-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared in the same manner as intermediate A-47. ESMS(M+1)=227.71.

A-55.(7S)-7-(tert-butyl)-2-chloro-4,8-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1: Methyl(S)-2-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)-3,3-dimethylbutanoate

The compound was prepared by reaction of methyl(S)-3,3-dimethyl-2-(methylamino)butanoate hydrochloride and2,4-dichloro-5-nitro-6-methylpyrimidine (965 mg, 4.64 mmol) followingthe procedure description in A-4 to provide the title product. 1H NMR(300 MHz, CDCl₃) δ 8.64 (s, 1H), 3.79 (d, J=0.9 Hz, 1H), 3.30 (s, 3H),2.36 (s, 3H), 1.03 (s, 8H). ESI-MS m/z calc. 268.1091, found 269.22(M+1)⁺. Chiral HPLC: >95% ee, Acq. Method. 20% MeOH-30% EtOH-50% Hex in20 mins on Chiral PAK IC column [α]^(22.9) _(D)=68.9° (c=1, CHCl₃).

A-56.(7S)-2-chloro-7-(2-hydroxyethyl)-4-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared in a similar manner as A-2 by reaction of2,4-dichloro-6-methyl-pyrimidin-5-amine (2 g, 11.23 mmol) and(2S)-2-amino-4-hydroxy-butanoic acid (1.338 g, 11.23 mmol) to providethe title product (1.2 g, 42% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.19(s, 1H), 8.18 (s, 1H), 4.54 (t, J=5.0 Hz, 1H), 4.18 (td, J=5.8, 1.9 Hz,1H), 3.53 (tdd, J=6.5, 4.8, 1.8 Hz, 2H), 2.22 (s, 3H), 1.87 (qd, J=6.5,2.9 Hz, 2H). ESI-MS m/z calc. 242.05705, found 243.1 (M+1)⁺.

A-57.(S)-2-chloro-4,8-dimethyl-7-(2,2,2-trifluoroethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of methyl3,3,3-trifluoro-2-(methylamino)propanoate and2,4-dichloro-5-nitro-6-methylpyrimidine following the proceduredescription in A-6 to provide the title product; ESI-MS m/z 269.16(M+1)⁺. The product was used without further characterization.

A-59.(7S)-2-chloro-7-((R)-1-methoxyethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of methyl(2S,3R)-3-methoxy-2-(methylamino)butanoate hydrochloride (14.07 g, 71.2mmol) and 2,4-dichloro-5-nitro-6-methylpyrimidine (14.1 g, 67.8 mmol)following the procedure description in A-6 to provide the title product(7S)-2-chloro-7-[(1R)-1-methoxyethyl]-4,8-dimethyl-5,7-dihydropteridin-6-one(10.5 g, 57%) 1H NMR (300 MHz, CDCl₃) δ 8.77 (s, 1H), 4.03 (d, J=5.0 Hz,1H), 3.74-3.59 (m, 1H), 3.28 (d, J=5.9 Hz, 6H), 2.37 (s, 3H), 1.28 (d,J=6.4 Hz, 3H). ESI-MS m/z calc. 270.08835, found 271.16 (M+1)⁺; 269.16(M−1)+. [α]_(D)=+32.14° (c=1.0, CHCl₃), temp 23.2° C.

A-60.(7S)-2-chloro-7-isobutyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(2S)-4-methyl-2-(methylamino)pentanoic acid (1.15 g, 7.920 mmol) and2,4-dichloro-6-methyl-pyrimidin-5-amine (1 g, 5.617 mmol) following theprocedure description in A-2 to provide the title product(7S)-2-chloro-7-isobutyl-4,8-dimethyl-5,7-dihydropteridin-6-one (570 mg,29%) 1H NMR (300 MHz, CDCl₃) δ 8.63 (s, 1H), 4.12 (d, J=6.6 Hz, 1H),3.16 (s, 3H), 2.47 (s, 3H), 1.79 (dp, J=12.9, 6.5 Hz, 1H), 1.67 (d,J=6.5 Hz, 1H), 0.99 (s, 2H), 0.95 (d, J=6.5 Hz, 3H). ESI-MS m/z calc.268.1091, found 269.13 (M+1)⁺.

A-61.(S)-2-chloro-7-(2-hydroxypropan-2-yl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1. Methyl(S)-2-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)-3-hydroxy-3-methylbutanoate

2,4-Dichloro-6-methyl-5-nitro-pyrimidine (377 mg, 1.758 mmol), methyl(2S)-3-hydroxy-3-methyl-2-(methylamino)butanoate (Trifluoroacetate salt)(388 mg, 1.410 mmol), and NaHCO₃ (762 mg, 9.071 mmol) were taken intocyclohexane (7 mL). The reaction flask was equipped with a Dean-Starktrap and the reaction was heated to 110° C. for 4 hours. Water anddichloromethane were added to the reaction. The phases were separated ona phase separator. The organic layer evaporated in vacuo and the residuepurified by column chromatography (SiO₂) eluting with a gradient ofheptanes to 80% ethyl acetate. ESI-MS m/z 333.12.

Step 2.(7S)-2-Chloro-7-(2-hydroxypropan-2-yl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

Methyl(S)-2-((2-chloro-6-methyl-5-nitropyrimidin-4-yl)(methyl)amino)-3-hydroxy-3-methylbutanoate(148 mg, 0.44 mmol) and platinum (58 mg, 0.008919 mmol) were placed in aParr bottle with THF (5 ml) and placed under 50 psi hydrogen for 3 days.To the reaction bis[(Z)-1-methyl-3-oxo-but-1-enoxy]-oxo-vanadium (3 mg,0.01131 mmol) was added to the reaction and placed on the Parr at 50 psifor 16 hours. The reaction was filtered and washed with MeOH and DCM.The volatiles were removed in vacuo and purified by columnchromatography (SiO₂) eluting with a gradient of heptanes to 80% ethylacetate. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 4.81 (s, 1H), 3.94(s, 1H), 3.21-3.09 (m, 4H), 2.22 (s, 3H), 1.20 (s, 3H), 1.01 (s, 3H);ESI-MS m/z 271.14.

A-62.2-chloro-7-(2-methoxyethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 4.28 (dd, J=6.6, 3.8 Hz, 1H),3.31-3.26 (m, 1H), 3.22-3.16 (m, 1H), 3.00 (s, 6H), 2.24 (s, 3H),2.08-2.00 (m, 1H), 1.99-1.93 (m, 1H). ESI-MS m/z 271.2 (M+1)⁺.

A-63.(7S)-7-(tert-butoxymethyl)-2-chloro-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of methyl(2S)-3-tert-butoxy-2-(methylamino)propanoate (2.56 g, 13.5 mmol) and2,4-dichloro-5-nitro-6-methylpyrimidine (2.8 g, 13.46 mmol) followingthe procedure description in A-6 to provide the title product (1.4 g,86% yield). 1H NMR (300 MHz, CDCl₃) δ 8.34 (s, 1H), 4.16 (t, J=2.6 Hz,1H), 3.75 (d, J=2.6 Hz, 2H), 3.15 (s, 3H), 2.32 (s, 3H), 1.04 (s, 8H).ESI-MS m/z calc. 298.11966, found 299.18 (M+1)⁺; [α]_(D)=+32.14° (c=1.0,CHCl₃), at 23.2° C. Chiral HPLC (ChiralPAK IC column; 20% methanol/30%ethanol/50% hexanes; 20 mins) Rt 4.56 mins (95% ee).

A-64.2′-chloro-4′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[oxetane-3,7′-pteridin]-6′-one

The compound was prepared by reaction of methyl3-(methylamino)oxetane-3-carboxylate and2,4-dichloro-5-nitro-6-methylpyrimidine following the proceduredescription in A-6 to provide the title product (41% yield). 1H NMR (400MHz, DMSO-d6) δ 2.23 (s, 3H), 3.36 (s, 3H), 4.81 (d, J=7.6 Hz, 2H), 5.01(d, J=7.2 Hz, 2H), 10.55 (s, 1H). ESI-MS m/z calc. 255.2 (M+1)⁺

A-65.2′-chloro-3,3-difluoro-4′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-pteridin]-6′-one

The compound was prepared by reaction of methyl3,3-difluoro-1-(methylamino)cyclobutane-1-carboxylate and2,4-dichloro-5-nitro-6-methylpyrimidine following the proceduredescription in A-6 to provide the title product. 1H NMR (400 MHz,DMSO-d6) δ 10.72 (s, 1H), 3.43-3.35 (m, 2H), 3.35-3.28 (m, 2H), 3.16 (s,3H), 2.28 (s, 3H). ESI-MS m/z calc. 289.2 (M+1)⁺

A-66.(7S)-2-chloro-7-(1-methoxycyclobutyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction methyl2-(1-methoxycyclobutyl)-2-(methylamino)acetate (5.5 g, 24.6 mmol) and2,4-dichloro-5-nitro-6-methylpyrimidine 5.56 g, 25.9 mmol) following theprocedure description in A-6 to provide the title product as a pair ofenantiomers. The enantiomers were separated by SFC (Cellulose-2, 20×250mm; 40% Ethanol (5 mM Ammonia)/60% CO₂, isocratic; 80 ml/min) to affordthe title product (3.86 g). 1H NMR (300 MHz, CDCl₃) δ 8.66 (s, 1H),4.28-4.15 (m, 1H), 3.25 (s, 3H), 2.51-2.13 (m, 6H), 2.00-1.65 (m, 3H).ESI-MS m/z calc. 296.104, found 297.04 (M+1)⁺; [α]D=17.08°, temp=25.1°C. Chiral HPLC: SFC Cellulose-2 column, 4.6 mm×100 mm, 40% EtOH (5 mMammonia)/60% CO₂ isocratic gradient, 1 ml/min; 6 min run) Rt 1.04 mins.(97% ee).

A-67.2′-chloro-4′,8′-dimethyl-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

The compound was prepared by reaction methyl3-(methylamino)tetrahydrofuran-3-carboxylate and2,4-dichloro-5-nitro-6-methylpyrimidine following the proceduredescription in A-6 to provide the title product as a racemic mixture. 1HNMR (400 MHz, DMSO-d6) δ 2.22-2.30 (m, 4H), 2.47 (t, J=4.0 Hz, 1H), 3.01(s, 3H), 3.70 (q, J=7.6 Hz, 1H), 4.02 (d, J=10.0 Hz, 1H), 4.08-4.16 (m,2H), 10.59 (s, 1H); ESI-MS m/z 269.1 (M+1)⁺.

A-68.(7S)-2-chloro-7-(1-methoxycyclopropyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of methyl(2S)-2-(1-methoxycyclopropyl)-2-(methylamino)acetate hydrochloride (840mg, 4.006 mmol) and 2,4-dichloro-5-nitro-6-methylpyrimidine (820 mg,3.942 mmol) following the procedure description in A-6 to provide thetitle product 1H NMR (300 MHz, CDCl₃) δ 8.23 (s, 1H), 3.68 (s, 1H), 3.28(s, 3H), 3.13 (s, 3H), 2.36 (s, 3H), 1.17-1.07 (m, 1H), 1.06-0.94 (m,2H), 0.89-0.73 (m, 1H). ESI-MS m/z calc. 282.08835, found 283.1 (M+1)⁺.[α]_(D)=+10.5° (c=1.0; CHCl₃) at 24° C.

A-69 & A-70.(7R)-2-chloro-7-(methoxymethyl)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand(7S)-2-chloro-7-(methoxymethyl)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of methyl3-methoxy-2-methyl-2-(methylamino)propanoate (6 g, 30.3 mmol) and2,4-dichloro-5-nitro-6-methylpyrimidine (6 g, 28.85 mmol) following theprocedure description in A-4 to provide the title product as a mixtureof enantiomers. The enantiomers were separated by SFC (Cellulose-2,20×250 mm; 40% Ethanol (5 mM Ammonia)/60% CO₂, isocratic; 80 ml/min) 1HNMR (300 MHz, CDCl₃) δ 8.22 (s, 1H), 3.81 (d, J=9.9 Hz, 1H), 3.58 (d,J=9.9 Hz, 1H), 3.32 (s, 3H), 3.14 (s, 3H), 2.33 (s, 3H), 1.56 (s, 3H).ESI-MS m/z calc. 270.08835, found 271.1 (M+1)⁺.

Enantiomer A: [α]D=+34.32°, temp=22.8° C. (c=1, MeOH). Chiral SFC(Cellulose-2, 4.6×100 mm; 40% Ethanol (5 mM Ammonia)/60% CO₂; Isocratic,1 ml/min) Rt 0.826 mins. (99.8% ee).

Enantiomer B: [α]D=−23.7°, temp=23.7° C. (c=1, MeOH). Chiral SFC(Cellulose-2, 4.6×100 mm; 40% Ethanol (5 mM Ammonia)/60% CO₂; Isocratic,1 ml/min) Rt 0.996 mins. (94.6% ee).

A-71.2-chloro-4,8-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared following the procedure reported for A-6 viareaction of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (1.04 g, 4.850mmol) and methyl 2-(methylamino)-2-(1-methylpyrazol-4-yl)acetatehydrochloride (853 mg, 3.883 mmol) to provide the title product. 1H NMR(400 MHz, DMSO-d6) δ 10.46 (s, 1H), 7.55 (s, 1H), 7.21 (t, J=5.3 Hz,1H), 5.11 (s, 1H), 3.69 (s, 3H), 2.87 (d, J=17.1 Hz, 3H) 2.24 (s, 3H).ESI-^(M) S m/z calc. 292.08392

A-72.(S)-7-((S)-1-(tert-butoxy)ethyl)-2-chloro-4,8-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1: MethylO-(tert-butyl)-N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-allothreoninate

Methyl (2S,3R)-3-tert-butoxy-2-(methylamino)butanoate (2.65 g, 13 mmol),2,4-dichloro-6-methyl-5-nitro-pyrimidine (4.85 g, 23.32 mmol), andNaHCO₃(3.3 g, 39.28 mmol) and stirred at room temperature for 16 hours.After filtration to remove the solid, the solution was concentrated andthe crude product was purified by column chromatography (SiO₂, 40 g)eluting with a gradient of 0-30% EtOAc in Hexanes to give the titleproduct as a sticky oil (2 g, 23% yield). 1H NMR (400 MHz, CDCl₃) δ 5.49(d, J=4.0 Hz, 1H), 4.53 (qd, J=6.3, 3.9 Hz, 1H), 3.78 (s, 3H), 3.13 (s,3H), 2.48 (s, 3H), 1.24 (d, J=6.3 Hz, 3H), 1.18 (s, 9H). ESI-MS m/zcalc. 374.1357, found 375.52 (M+1)⁺

Step 2:(S)-7-((S)-1-(tert-butoxy)ethyl)-2-chloro-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

MethylO-(tert-butyl)-N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-allothreoninate(2 g) was dissolved followed by the addition of Platinum (165 mg, 0.025mmol) on wood and hydrogenated for 4 days. The reaction was filteredthrough Celite to remove the catalyst. The filtrate was evaporated invacuo to provide the title product as a white solid (1.7 g). 1H NMR (300MHz, CDCl₃) δ 8.35 (s, 1H), 4.15-3.99 (m, 1H), 3.93 (d, J=4.1 Hz, 1H),3.31 (d, J=1.8 Hz, 3H), 2.35 (d, J=2.0 Hz, 3H), 1.60 (d, J=2.0 Hz, 5H),1.32 (dd, J=6.4, 2.0 Hz, 3H), 1.13-0.98 (m, 9H). ESI-MS m/z calc.312.1353, found 313.28 (M+1) 7. Chiral HPLC: (Chiralpak IC column, 20%EtOH/30% EtOH/50% hex, 20 min run, 95% ee; [α]_(D)=+60.44° (chloroform;c=0.5@24.5° C.).

A-73.(7S)-2-chloro-7-(2-hydroxyethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

Iodomethane (1.1 ml, 17.5 mmol) was added to a mixture of(7S)-2-chloro-7-(2-hydroxyethyl)-4-methyl-7,8-dihydropteridin-6(5H)-one(2 g, 8 mmol) and cesium carbonate (7.78 g, 23.9 mmmol) in DMF (25 ml)and stirred for 16 hours. Water was added to the reaction mixture andextracted with ethyl acetate (3×10 ml). The combined extracts werewashed with brine (20 ml), and water (2×20 ml). The organic extract wasdried over anhydrous sodium sulfate, filtered, and evaporated in vacuoto afford the title product. 1H NMR (300 MHz, DMSO-d6) δ 4.60 (t, J=4.8Hz, 1H), 4.27 (dd, J=7.0, 5.8 Hz, 1H), 3.34 (m, 2H), 3.24 (s, 3H), 3.05(s, 3H), 2.40 (s, 3H), 1.68 (m, 2H). ESI-MS m/z calc. 268.1091, found269.22 (M+1)⁺.

A-74.(S)-7-((R)-1-(tert-butoxy)ethyl)-2-chloro-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared in a similar manner as A-72. 1H NMR (300 MHz,CDCl₃) δ 8.35 (s, 1H), 4.15-3.99 (m, 1H), 3.93 (d, J=4.1 Hz, 1H), 3.31(d, J=1.8 Hz, 3H), 2.35 (d, J=2.0 Hz, 3H), 1.60 (d, J=2.0 Hz, 5H), 1.32(dd, J=6.4, 2.0 Hz, 3H), 1.13-0.98 (m, 9H). ESI-MS m/z 313.28 (M+1)⁺;[α]=60.44° (c=0.5, CHCl₃) at 24.2° C. Chiral HPLC: Chiralpak IC column(20% methanol/30% ethanol/50% hexanes)>95% ee.

A-75.(7R)-2-Chloro-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared in the same manner as intermediate A-3 toprovide the title product.(7R)-2-chloro-7-ethyl-8-isopropyl-5,7-dihydropteridin-6-one (10.8 g,77%) 1H NMR (300 MHz, CDCl₃) δ 9.12 (s, 1H), 7.67 (s, 1H), 4.61 (p,J=6.8 Hz, 1H), 4.29 (dd, J=7.4, 3.3 Hz, 1H), 2.13-1.92 (m, 1H), 1.81(dt, J=14.5, 7.4 Hz, 1H), 1.40 (dd, J=11.4, 6.8 Hz, 6H), 0.96 (t, J=7.5Hz, 3H). ESI-MS m/z calc. 254.09344, found 255.16 (M+1)⁺; 253.16 (M−1)+.

A-76. (S)-2-Chloro-7-ethyl-8-isopropyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared in the same manner as intermediate A-4 toprovide the title product. 1H NMR (300 MHz, CDCl₃) δ 9.24 (s, 1H), 7.68(s, 1H), 4.61 (p, J=6.8 Hz, 1H), 4.29 (dd, J=7.5, 3.3 Hz, 1H), 2.00(ddt, J=15.1, 7.6, 3.8 Hz, 1H), 1.81 (dt, J=14.5, 7.4 Hz, 1H), 1.40 (dd,J=11.3, 6.8 Hz, 6H), 0.96 (t, J=7.5 Hz, 3H). ESI-MS m/z calc. 254.09344,found 255.16 (M+1)⁺; 253.16 (M−1)+; [α]_(D)=+207.580 (c=1.0, CHCl₃).

A. Preparation of Side Chain Amine Intermediates

The following side chain amines were prepared by the following reactionschemes. A representative procedure follows for each scheme.

Method A: Synthesis of (1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride (B-2) Via Scheme A Step 1: Ethyl1-(4-fluorobenzyl)-1H-pyrazole-4-carboxylate

Sodium hydride (60% oil dispersion; (2.869 g, 71.7 mmol)) was addedportion wise to a cold (0° C.) solution of ethyl1H-pyrazole-4-carboxylate (6.7 g, 47.81 mmol) in DMF (70 mL). Themixture was stirred for 1 hour at 0° C. followed by the addition of1-(bromomethyl)-4-fluoro-benzene (10.85 g, 57.38 mmol). The reaction waswarmed to room temperature and stirred for 18 hours. The reactionmixture was poured into water and the resulting precipitate wascollected by vacuum filtration, washed with water, and dried undervacuum at 50° C. for 20 hours to afford the title compound, wt. 8.3 g(70% yield); 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=0.7 Hz, 1H), 7.87(d, J=0.7 Hz, 1H), 7.34 (dd, J=8.6, 5.6 Hz, 2H), 7.18 (t, J=8.9 Hz, 2H),5.35 (s, 2H), 4.20 (q, J=7.1 Hz, 2H), 1.25 (t, J=7.1 Hz, 3H).

Step 2: (1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methanol

A solution of ethyl 1-[(4-fluorophenyl)methyl]pyrazole-4-carboxylate (10g, 40.28 mmol) in THE (50 mL) was added dropwise to a cooled (0° C.)solution of Lithium aluminum hydride (60 mL of 1 M, 60 mmol) in THF.After stirring for 1 hour at 0° C., the reaction was warmed to roomtemperature for 30 minutes, then quenched with 1N HCl until a clearsolution was obtained. The clear solution was extracted with ethylacetate (3×50 ml). The combined extracts were washed with water andbrine, dried over sodium sulfate, filtered, and evaporated in vacuo toafford the crude product, wt. 7.5 g (90% yield); 1H NMR (400 MHz,Methanol-d4) δ 7.64 (s, 1H), 7.49 (s, 1H), 7.25 (dd, J=8.8, 5.3 Hz, 2H),7.05 (t, J=8.8 Hz, 2H), 5.28 (s, 2H), 4.49 (s, 2H); ESMS (M+11)=207.0.

Step 3: 4-(Azidomethyl)-1-(4-fluorobenzyl)-1H-pyrazole

A mixture of (1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methanol (8 g, 38.8mmol) and (azido(phenoxy)phosphoryl)oxybenzene (16.0 g, 12.5 mL, 58.2mmol) was dissolved in dry THE (100 ml) and cooled to 0° C. underNitrogen. DBU (8.7 mL, 58.2 mmol) was added to the reaction and stirredfor 2 h at 0° C. and then warmed to room temperature for 16 hours. Thereaction mixture was diluted with ethyl acetate and washed with water(2×50 mL) and 5% HCl (10 mL). The organic layer was concentrated invacuo and purified by column chromatography eluting with a gradient of10-35% ethyl acetate in hexanes to provide the title compound, wt. 7.2 g(90% yield); 1H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 7.41 (s, 1H),7.25-7.16 (m, 2H), 7.12-6.96 (m, 2H), 5.28 (s, 2H), 4.23 (s, 2H).

Step 4: (1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methanamine

Triphenylphosphine (13.6 g, 51.9 mmol) and water (8 ml) were added to asolution of 4-(azidomethyl)-1-[(4-fluorophenyl)methyl]pyrazole (8 g,34.60 mmol) in dichloromethane (100 mL) and stirred at room temperaturefor 16 hours; 30 mL of 1N HCl was added to the reaction mixture. Theorganic layer was separated and discarded. The aqueous layer was washedwith dichloromethane and separated. The aqueous layer was evaporated invacuo resulting in a white solid. The HCl salt of the product wasdissolved in methanol and precipitated out of solution by diethyl ether(5 times the methanol volume). The precipitate was collected by vacuumfiltration and dried over vacuum at 50° C. to provide the desiredproduct, wt. 6.4 g (76% yield); 1H NMR (400 MHz, DMSO-d6) δ 8.15 (brs,3H), 7.88 (s, 1H), 7.56 (s, 1H), 7.32 (dt, J=8.0, 3.3 Hz, 2H), 7.18 (td,J=8.9, 1.2 Hz, 2H), 5.32 (s, 2H), 3.87 (q, J=5.7 Hz, 2H).

Method B: Synthesis of(1-(3,4,5-Trifluorobenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride(B-23) Via Scheme B Step 1: tert-Butyl((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)carbamate

tert-Butyl N-(1H-pyrazol-4-ylmethyl)carbamate (6.07 g, 29.85 mmol) wasdissolved in 60 ml of anhydrous DMF (60 ml) to give a clear palesolution, The solution was cooled to 2° C. and sodium hydride (1.253 g,31.34 mmol) was added to the mixture portion wise and stirred for 30mins. 5-(Bromomethyl)-1,2,3-trifluoro-benzene (7.540 g, 32.84 mmol) wasadded dropwise over 10 minutes. The reaction was stirred at 2° C. for 2hours then warmed to room temperature over 2 hours. The reaction waspoured onto 180 ml of cold water and extracted with ethyl acetate (2×200ml). The combined ethyl acetate extracts was washed with brine, driedover sodium sulfate, filtered, and evaporated in vacuo to provide thecrude product. The reaction was purified by column chromatography (SiO₂;220 g column) eluting with a gradient of 0-90% ethyl acetate in hexanes.The desired fractions were evaporated in vacuo to provide the desiredproduct as a viscous oil that crystallizes upon standing. Wt. 9.1 g; 1HNMR (300 MHz, CDCl₃) δ 7.49 (s, 1H), 7.38 (s, 1H), 6.87-6.73 (m, 2H),5.19 (s, 2H), 4.72 (s, 1H), 4.17 (d, J=5.8 Hz, 2H), 1.45 (s, 9H).

Step 2: (1-(3,4,5-Trifluorobenzyl)-1H-pyrazol-4-yl)methanamine

tert-Butyl ((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)carbamate(9.1 g, 26.66 mmol) was dissolved in dioxane (64 mL). A solution of 4 NHCl (67 ml, 267 mmol) was added to the solution and heated at 55° C. for3 hours. A white precipitate formed. Approximately 2/3 of the dioxanewas evaporated in vacuo followed by the addition of diethyl ether andstirred for 30 minutes. The white precipitate was collected by vacuumfiltration and dried under vacuum at 50° C. for 20 hours to afford 7.4 gof the product as the hydrochloride salt. (100% yield); 1H NMR (300 MHz,DMSO-d6) δ 8.27 (s, 3H), 7.96 (s, 1H), 7.62 (s, 1H), 7.19 (dd, J=8.7,6.9 Hz, 2H), 5.36 (s, 2H), 3.88 (q, J=5.6 Hz, 2H).

Method C: Synthesis of(1-(2,3-Dihydro-1H-inden-2-yl)-1H-pyrazol-4-yl)methanamine (B-44) viascheme C Step 1:1-(2,3-Dihydro-1H-inden-2-yl)-1H-pyrazole-4-carbonitrile

A mixture of sodium (Z)-2-cyano-3,3-diethoxyprop-1-en-1-olate (298 mg,1.54 mmol) and (2,3-dihydro-1H-inden-2-yl)hydrazine methane sulfonicacid salt (343 mg, 1.40 mmol) was taken into 6 ml of ethanol.Concentrated HCl (270 ul, 2.83 mmol) was added to the mixture and heatedto 80° C. for 2 hours. Solvent was removed to 12 volume, water added tothe mixture, and the resulting solid collected and dried to afford thetitle compound, wt. 246 mg (87% yield). 1H NMR (300 MHz, CDCl₃) δ 7.81(s, 1H), 7.74 (s, 1H), 7.34-7.20 (m, 4H), 5.24 (tt, J=7.5, 5.0 Hz, 1H),3.56 (dd, J=16.3, 7.5 Hz, 2H), 3.36 (dd, J=16.3, 5.0 Hz, 2H); ESMS(M+1)=210.12.

Step 2: (1-(2,3-Dihydro-1H-inden-2-yl)-1H-pyrazol-4-yl)methanamine

1-(2,3-Dihydro-1H-inden-2-yl)-1H-pyrazole-4-carbonitrile (240 mg, 1.15mmol) was taken into methanol (30 ml). Rainey nickel (40 mg, 0.68 mmol)was added and the reaction hydrogenated under hydrogen (50 psi) for 3hours. The reaction was filtered and the filtrate evaporated in vacuo toafford the title product, 237 mg (97% yield). 1H NMR (400 MHz, CDCl₃) δ7.35 (s, 1H), 7.17 (dd, J=11.4, 7.2 Hz, 5H), 5.17-4.96 (m, 1H), 3.75 (s,1H), 3.40 (dd, J=16.1, 7.6 Hz, 2H), 3.31-3.09 (m, 2H); ESMS(M+1)=214.22.

Method D: (1-(3,4-dimethoxybenzyl)-1H-pyrazol-3-yl)methanaminehydrochloride Step 1:(E&Z)-2-(4-(Dimethylamino)-2-oxobut-3-en-1-yl)isoindoline-1,3-dione

A mixture of 2-(2-oxopropyl)isoindoline-1,3-dione (2.03 g, 10 mmol) and1,1-dimethoxy-N,N-dimethyl-methanamine (1.3 ml, 10 mmol) was irradiatedby microwave at 180° C. for 20 minutes. The resulting solid wasrecrystallized from ethanol to provide the title product as a mixture ofcis- & trans-isomers 2.34 g (91% yield). ESMS (M+1)=259.10.

Step 2:2-((1-(3,4-Dimethoxybenzyl)-1H-pyrazol-3-yl)methyl)isoindoline-1,3-dione

(E & Z)-2-(4-(Dimethylamino)-2-oxobut-3-en-1-yl)isoindoline-1,3-dione (1g, and (3,4-dimethoxybenzyl)hydrazine (1 g, mmol) was taken into ethanol(10 ml) and conc HCl (1 ml) and heated to reflux for 3 hours. Thereaction was evaporated in vacuo and the residue purified by columnchromatography (SiO₂) eluting with a gradient of 0-10% methanol indichloromethane to give the desired product as a yellow solid, wt. 1.1g. 1H NMR (400 MHz, CDCl₃) δ 7.78-7.71 (m, 2H), 7.71-7.64 (m, 2H), 7.52(d, J=1.8 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.54-6.49 (m, 1H), 6.50-6.42(m, 2H), 5.49 (s, 2H), 4.85 (s, 2H), 3.78 (d, J=0.8 Hz, 3H), 3.73 (d,J=0.8 Hz, 3H).

Step 3: (1-(3,4-dimethoxybenzyl)-1H-pyrazol-3-yl)methanaminehydrochloride

A mixture of2-((1-(3,4-dimethoxybenzyl)-1H-pyrazol-3-yl)methyl)isoindoline-1,3-dione(1.1 g, 2.92 mmol) and methylamine (2M solution in methanol; 7.3 ml,14.6 mmol) in methanol was refluxed for 2 hours. The solvent was removedin vacuo. The compound was taken into 2M HCl in methanol andprecipitated with the addition of diethyl ether to provide the titleproduct, wt. 638 mg (89% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.61(d, J=2.0 Hz, 1H), 6.91 (d, J=8.2 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H),6.72-6.64 (m, 1H), 6.59-6.49 (m, 1H), 5.40 (s, 2H), 4.20 (s, 2H), 3.80(s, 3H), 3.77 (s, 3H).

B-1. (1-(4-Fluoro-2-methoxybenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.14 (s, 3H), 7.76 (s,1H), 7.53 (s, 1H), 7.05 (dd, J=8.3, 6.9 Hz, 1H), 6.96 (dd, J=11.3, 2.4Hz, 1H), 6.74 (td, J=8.5, 2.5 Hz, 1H), 5.22 (s, 2H), 3.86 (dd, J=10.1,4.3 Hz, 2H), 3.84 (d, J=4.4 Hz, 3H); ESMS (M+1)=236.10.

B-2. (1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method A. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 3H), 7.89 (s,1H), 7.57 (s, 1H), 7.32 (dd, J=8.6, 5.6 Hz, 2H), 7.18 (t, J=8.9 Hz, 2H),5.32 (s, 2H), 3.86 (q, J=5.8 Hz, 2H); ESMS (M+1)=206.36.

B-3. (1-(3-Fluorobenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.73(s, 1H), 7.32 (dt, 1H), 7.05 (m, J=3H), 5.41 (s, 2H), 4.06 (s, 2H); ESMS(M+1)=206.19.

B-4. (1-(1-(4-Fluorophenyl)ethyl)-1H-pyrazol-4-yl)methanamine

Prepared by Method A. 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 3H), 7.90 (s,1H), 7.58 (s, 1H), 7.38-7.27 (m, 2H), 7.16 (td, J=8.7, 1.4 Hz, 2H), 5.65(q, J=7.1 Hz, 1H), 3.86 (q, J=5.7 Hz, 2H), 1.76 (dd, J=7.1, 1.3 Hz, 3H).

B-5. (1-(4-(Trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=256.19

B-6. (1-(3-(Trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=256.26

B-7. (1-(2-(Trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.90 (s, 1H),7.81-7.72 (m, 2H), 7.64-7.45 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 5.62 (s,2H), 4.08 (s, 2H); ESMS (M+1)=256.17

B-8. 4-((4-(Aminomethyl)-1H-pyrazol-1-yl)methyl)benzonitrilehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.85 (d, J=0.8 Hz,1H), 7.67 (d, J=8.3 Hz, 2H), 7.61 (d, J=0.8 Hz, 1H), 7.39-7.28 (m, 2H),5.42 (s, 2H), 4.01 (s, 2H); ESMS (M+1)=213.12

B-9. (1-(2-Isopropylbenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=230.43

B-10. (1-(3-Isopropylbenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=230.39

B-11. (1-(3,4-Difluorobenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=224.11

B-12. (1-(2,4-Difluorobenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=224.07

B-13. (1-(2-Chloro-4-fluorobenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.71(s, 1H), 7.36-7.18 (m, 2H), 7.17-7.04 (m, 1H), 5.48 (s, 2H), 4.06 (s,2H); ESMS (M+1)=240.1

B-14. (1-(4-Fluoro-2-methylbenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.83 (d, J=14.2Hz, 2H), 7.15 (dd, J=8.5, 5.8 Hz, 1H), 7.05-6.86 (m, 2H), 5.42 (s, 2H),4.06 (s, 2H), 2.31 (s, 3H); ESMS (M+1)=220.2.

B-15.(1-(4-Fluoro-2-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.88 (s, 1H), 7.71(s, 1H), 7.55 (dd, J=9.0, 2.7 Hz, 1H), 7.36 (td, J=8.3, 2.7 Hz, 1H),7.13 (dd, J=8.8, 5.3 Hz, 1H), 5.57 (s, 2H), 4.07 (s, 2H); ESMS(M+1)=274.23.

B-16. (1-(4-Fluoro-3-methoxybenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.93 (s, 1H), 7.71(s, 1H), 7.14-6.93 (m, 2H), 6.84 (ddd, J=8.3, 4.1, 2.0 Hz, 1H), 5.34 (s,2H), 4.05 (s, 2H), 3.85 (d, J=1.2 Hz, 3H); ESMS (M+1)=236.09

B-17. (1-(3-Fluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=236.0

B-18. 2-((4-(Aminomethyl)-1H-pyrazol-1-yl)methyl)-5-fluorobenzonitrilehydrochloride

Prepared by Method B. ESMS (M+1)=231.18

B-19. (1-(Benzo[d][1,3]dioxol-5-ylmethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=232.18

B-20. (1-(3,5-Difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.33(s, 3H), 7.95 (s, 1H), 7.61 (s, 1H), 7.11-6.92 (m, 2H), 5.31 (s, 2H),3.96 (s, 3H), 3.78 (m, 2H); ESMS (M+1)=254.24.

B-21. (1-(2,4-Difluoro-3-methoxybenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 6.60 (s, 1H), 6.36(s, 1H), 5.78-5.62 (m, 2H), 4.09 (s, 2H), 2.76 (s, 2H), 2.66 (s, 3H);ESMS (M+1)=254.15.

B-22. (1-(2,3,4-Trifluorobenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.18 (br.s, 3H), 7.92(s, 1H), 7.58 (s, 1H), 7.41-7.26 (m, 1H), 7.23-7.08 (m, 1H), 5.43 (s,2H), 3.93 (br.s, 1H), 3.87 (q, J=5.7 Hz, 2H); 1H NMR (300 MHz,Methanol-d4) δ 7.66 (s, 1H), 7.50 (s, 1H), 7.15-6.94 (m, 2H), 5.36 (s,2H), 3.69 (s, 2H); ESMS (M+1)=242.14.

B-23. (1-(3,4,5-Trifluorobenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 3H), 7.95 (s,1H), 7.61 (s, 1H), 7.18 (dd, J=8.8, 6.7 Hz, 2H), 5.36 (s, 2H), 3.88 (q,J=5.6 Hz, 2H); ESMS (M+1)=242.13.

B-24. (1-(2,4,5-Trifluorobenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 3H), 7.90 (s,1H), 7.65-7.58 (m, 1H), 7.58 (s, 1H), 7.37 (ddd, J=10.9, 9.0, 6.8 Hz,1H), 5.36 (s, 2H), 3.88 (q, J=5.7 Hz, 2H); ESMS (M+1)=242.13.

B-25. (1-(4-Fluorophenethyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=220.11

B-26. (1-(3,4-Difluorophenethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=238.12

B-27. (1-(2,4-Difluorophenethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=238.12

B-28. (1-(3,4,5-Trifluorophenethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=256.00.

B-29. (1-(2,4,6-Trifluorophenethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=256.00.

B-30. (1-(3,5-Difluorophenethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=238.26.

B-31. (1-(4-Ethoxyphenethyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=246.18

B-32. (1-(3-(4-Fluorophenyl)propyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=234.12.

B-33. (1-(2-(4-Fluorophenoxy)ethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=236.14.

B-34.(1-((trans)-3-(4-Fluorophenyl)cyclobutyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.44 (s,1H), 7.30-7.17 (m, 2H), 7.02 (t, J=8.7 Hz, 2H), 4.94-4.78 (m, 1H), 3.79(s, 2H), 3.75 (m, 1H), 3.05-2.90 (m, 2H), 2.73-2.57 (m, 2H), 1.79 (s,2H). ESMS (M+1)=245.9

B-35. (1-(2-Cyclohexylethyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.96(s, 1H), 4.41-4.25 (m, 2H), 4.11 (s, 2H), 1.88-1.53 (m, 7H), 1.25 (dd,J=15.2, 8.2 Hz, 4H), 1.01 (t, J=11.1 Hz, 2H).

B-36. (1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.93(s, 1H), 4.21 (t, J=6.8 Hz, 2H), 3.92 (s, 2H), 3.68 (dd, J=11.4, 3.8 Hz,3H), 3.19-2.99 (m, 2H), 1.65 (q, J=6.4 Hz, 2H), 1.38 (dd, J=35.5, 11.9Hz, 4H), 1.23-0.89 (m, 3H).

B-37. (1-(2-(4,4-Difluorocyclohexyl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.86 (s, 1H), 7.69(s, 1H), 4.10 (d, J=7.2 Hz, 2H), 4.05 (s, 2H), 2.14-1.90 (m, 4H),1.89-1.71 (m, 1H), 1.65 (dd, J=14.0, 3.6 Hz, 2H), 1.43-1.22 (m, 2H).

B-38. (1-(Cyclobutylmethyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=166.14.

B-39. (1-((3,3-Difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, DMSO-d6) δ 8.12 (br s, 3H), 7.83(s, 1H), 7.55 (d, J=0.8 Hz, 1H), 4.24 (d, J=6.3 Hz, 2H), 3.87 (q, J=5.8Hz, 2H), 2.65-2.35 (m, 5H); ESMS (M+1)=202.10.

B-40. (1-(2-Cyclopentylethyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=194.18.

B-41. (1-(2-Cyclopropylethyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. ESMS (M+1)=166.14

B-42. (S)-(1-(2-Methylbutyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.89(s, 1H), 4.12 (dd, J=13.9, 6.7 Hz, 1H), 4.01 (d, J=2.2 Hz, 2H),4.00-3.92 (m, 1H), 1.98-1.76 (m, 1H), 1.38-1.18 (m, 1H), 1.18-0.95 (m,1H), 0.83 (t, J=7.4 Hz, 3H), 0.77 (d, J=6.7 Hz, 3H); ESMS (M+1)=168.07.

B-43. (1-(Bicyclo[2.2.1]heptan-2-ylmethyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared Method B. ESMS (M+1)=206.25.

B-44. (1-(2,3-Dihydro-1H-inden-2-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method C. 1H NMR (400 MHz, CDCl3) δ 7.35 (s, 1H), 7.17 (dd,J=11.4, 7.2 Hz, 5H), 5.17-4.96 (m, 1H), 3.75 (s, 1H), 3.40 (dd, J=16.1,7.6 Hz, 2H), 3.31-3.09 (m, 2H); ESMS (M+1)=214.22

B-45. 2-(4-(Aminomethyl)-1H-pyrazol-1-yl)-1-(4-fluorophenyl)ethan-1-onehydrochloride

Prepared by Method B. ESMS (M+1)=234.07

B-46.(1-(6-Fluoro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=232.13

B-47. (1-(3-(Trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method C. ESMS (M+1)=242.36.

B-48. (1-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method C ESMS (M+1)=210.36

B-49. (1-(3,4-Dimethoxybenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method D.

B-50. (1-(2-(4-Fluorophenyl)-2-methylpropyl)-1H-pyrazol-4-yl)methanamine

Prepared by Method A. 40% yield. ESMS (M+1)=248.16.

B-51. Preparation of(1-(3-(4-Fluorophenyl)cyclopentyl)-1H-pyrazol-4-yl)methanamine.

Step 1: 3-(4-Fluorophenyl)cyclopentan-1-one

A vial charged with [Rh(cod)Cl]₂ (180.2 mg, 0.3654 mmol) and(4-fluorophenyl)boronic acid (4.261 g, 30.45 mmol) was flushed withnitrogen. To the reaction vial was added sequentially, water (60 mL)(degassed for >1 hr with nitrogen) followed by sodium carbonate (2.582g, 24.36 mmol). The mixture was stirred under a nitrogen atmosphereuntil the sodium carbonate was fully dissolved (˜3 min).Cyclopent-2-en-1-one (1.0 g, 12.18 mmol) was added to the mixture. Theheterogeneous mixture was heated to 80° C. under a nitrogen atmosphere.

After 1 hr, the reaction was cooled to room temperature. The aqueousmixture was extracted with ethyl acetate (2×) and again withdichloromethane (2×). The combined organic layers were dried overanhydrous sodium sulfate, filtered through a short plug of silica gel(˜8 gram) and concentrated to provide the desired product wt. 2.09 g,96%. yield. 1H NMR (400 MHz, CDCl₃) δ 7.23-7.14 (m, 1H), 7.01 (dd,J=12.0, 5.3 Hz, 1H), 3.39 (ddd, J=18.1, 11.1, 6.9 Hz, 1H), 2.66 (dd,J=18.0, 7.6 Hz, 1H), 2.54-2.36 (m, 1H), 2.29 (dt, J=11.1, 9.9 Hz, 1H),2.03-1.84 (m, 1H).

Step 2: 3-(4-Fluorophenyl)cyclopentan-1-ol

Sodium borohydride (424.5 mg, 11.2 mmol) was added to a solution of3-(4-fluorophenyl)cyclopentan-1-one (2.0 g, 11.22 mmol) in anhydrousmethanol (40.00 mL) at 0 C. The solution was kept at 0° C. for 2 hours.After 3 hrs, the mixture was evaporated in vacuo and the crude materialwas partitioned between dichloromethane and 2N HCl. The aqueous layerwas extracted with dichloromethane. and the combined organic extractswere dried over Na₂SO₄, concentrated, and filtered through a shortsilica plug to give a pale orange oil. (1.94 g) NMR indicated thismaterial was a mixture of 41:59 of trans:cis

Step 3: Ethyl1-(3-(4-fluorophenyl)cyclopentyl)-1H-pyrazole-4-carboxylate

A stirred solution of 3-(4-fluorophenyl)cyclopentanol (1.87 g, 10.38mmol) and ethyl 1H-pyrazole-4-carboxylate (1.631 g, 11.64 mmol) in THE(46 mL) was dried over 3A molecular sieves for ˜3 hours to remove tracesof water. The solution was transferred to a dry vial charged withtriphenylphosphine (4.03 g, 15.4 mmol) and the solution was stirred atroom temperature.

Diethyl azodicarboxylate (6.4 mL of 40% w/v, 14.7 mmol) was addeddropwise over 20 minutes. The yellow solution was stirred at roomtemperature for 30 minutes, then heated to 60° C. for 2 hours. Thereaction was cooled to room temperature and stirred overnight. Thereaction was evaporated in vacuo. The crude product was purified byflash chromatography (SiO₂, gradient elution 30-100% EtOAc in hexanes)to provide 2.09 g of the title product as a mixture of cis and transisomers (45:55 cis:trans). ESMS (M+1)=303.08.

Step 4: (1-(3-(4-Fluorophenyl)cyclopentyl)-1H-pyrazol-4-yl)methanol

A 1 M solution of lithium aluminum hydride (14.00 mL, 14.00 mmol) wasadded dropwise to a cooled (0° C.) solution of ethyl1-(3-(4-fluorophenyl)cyclopentyl)-1H-pyrazole-4-carboxylate (2.09 g, 6.9mmol) in THF (27 mL). After addition, the mixture was slowly warmed toroom temperature. After 6 hours, the reaction was quenched with theaddition of water (0.5 mL), 15% NaOH (0.5 mL) and water (0.5 mL).Diethyl ether was added to the reaction and the mixture was stirred for˜30 minutes. The mixture was filtered through a silica plug to removethe aluminum salts. The filtrate was evaporated in vacuo to provide theproduct as a colorless viscous oil (1.72 g). 1H NMR (400 MHz, CDCl₃) δ7.47 (s, 1H), 7.42 (s, 1H), 7.15 (ddd, J=14.0, 8.5, 4.3 Hz, 2H), 6.92(t, J=8.7 Hz, 2H), 4.86-4.64 (m, 1H), 3.40 (tt, J=9.9, 7.5 Hz, 0.6H),3.10 (tt, J=11.5, 7.1 Hz, 0.4H), 2.62-1.54 (m, 6H).

Step 5: 4-(Azidomethyl)-1-(3-(4-fluorophenyl)cyclopentyl)-1H-pyrazole

To a cooled (0° C.) solution of(1-(3-(4-fluorophenyl)cyclopentyl)-1H-pyrazol-4-yl)methanol (1.72 g,6.608 mmol) in dry THF (35 mL) was added DBU (1.257 g, 1.235 mL, 8.260mmol) followed by dropwise addition of DPPA (2.18 g, 1.7 mL, 7.93 mmol).The mixture was kept at 0° C. for 2 hours and allowed to warm to roomtemperature overnight. The reaction was partitioned betweendichloromethane and saturated sodium bicarbonate. The aqueous layer wasextracted with dichloromethane. The combined organic extracts were driedover anhydrous sodium sulfate, filtered, and concentrated in vacuo. Thecrude product was purified by flash chromatography (SiO₂) eluting with agradient of 0-100% ethyl acetate in hexanes). The desired fractions werecombined and evaporated to provide the product as a mixture ofdiastereomers. NMR showed a clean mixture of diastereomers with a ratioof trans cis=˜60:40.

Step 6: (1-(3-(4-fluorophenyl)cyclopentyl)-1H-pyrazol-4-yl)methanamine

A solution of 4-(azidomethyl)-1-(3-(4-fluorophenyl)cyclopentyl)pyrazole(1.44 g, 5.047 mmol) in dry tetrahydrofuran (7 mL) was added dropwise toa solution of lithium aluminum hydride (10.17 mL of 1 M, 10.17 mmol) intetrahydrofuran at room temperature over 5 minutes (reaction turnedyellow during addition).

After 3 hours, the reaction was quenched with the addition of 0.1 mL ofwater, 0.1 mL of 15% NaOH, and 0.3 mL of water. The mixture was dilutedwith diethyl ether (15 mL) and stirred at room temperature. The reactionwas filtered, to remove the aluminum salts, and rinsed with severalportions of diethyl ether. The filtrate was evaporated in vacuo toprovide the desired product, Wt. 586 mg. 1H NMR confirmed product as amixture of diastereomers. 1H NMR (300 MHz, CDCl₃) δ 7.49 (s, 1H), 7.44(s, 1H), 7.27-7.17 (m, 2H), 7.00 (t, J=8.7 Hz, 2H), 4.94-4.68 (m, 1H),3.81 (d, 2H), 3.48 (m, 0.6H), 3.18 (m, 0.4H), 2.72-1.91 (m, 6H). (trans:cis=˜ 60:40).

B-52.(1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B in 2 steps

Step 1: tert-butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate

tert-Butyl N-(1H-pyrazol-4-ylmethyl)carbamate (18.9 g, 95.83 mmol) and5-(chloromethyl)-2-(trifluoromethyl)pyridine (19.67 g, 100.6 mmol) wastaken into 190 ml of DMF and cooled to 0° C. Sodium hydride (60% w/w oildispersion; 4.22 g, 105.4 mmol) was added to the mixture portionwisekeeping the temperature below 10° C. The mixture was stirred overnightallowing the temperature to warm to room temperature. Water (1 L) wasadded to the reaction mixture and a white precipitate formed. Themixture was stirred for 30 mins then filtered and the filter cake washedwith water and heptane and dried under vacuum at 50° C. for 18 hours toprovide the title compound, wt. 33.5 g (98% yield). 1H NMR (300 MHz,CDCl₃) δ 8.62 (s, 1H), 7.74-7.61 (m, 2H), 7.52 (s, 1H), 7.44 (s, 1H),5.38 (s, 2H), 4.74 (s, 1H), 4.19 (d, J=5.8 Hz, 2H), 1.46 (s, 9H).

Step 2:(1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

tert-Butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(33.5 g, 94 mmol) was dissolved into 200 ml of dioxane and 4M HCl indioxane (235 ml) was added to the solution. The solution was stirred atroom temperature for 3 hours followed by heating at 50° C. for 2 hours.The dioxane was evaporated in vacuo to afford a viscous gum.Dichloromethane (300 ml) was added to the gum and stirred at roomtemperature for 30 mins resulting in formation of a solid. The solid wascollected by vacuum filtration, washed with dichloromethane and driedunder vacuum at 50° C. for 18 hours to afford the title product, wt.31.2 g (90.8% yield). ¹H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.07 (s,3H), 7.96 (s, 1H), 7.92 (s, 2H), 7.59 (s, 1H), 5.54 (s, 2H), 3.91 (d,J=4.0 Hz, 2H); F19 NMR (282.4 MHz, DMSO-d6) −66.38, −73.62 ppm; ESMS(M+1)=257.14.

B-53. (1-((6-Fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.16 (d, J=2.4 Hz,1H), 7.96-7.82 (m, 2H), 7.65 (s, 1H), 7.08 (dd, J=8.5, 2.6 Hz, 1H), 5.42(s, 2H), 4.05 (s, 2H).

B-54.(1-((6-Fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 7.97 (bs, 4H), 7.83(d, J=0.8 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.11-7.04 (m, 1H), 5.39 (s,2H), 3.90 (q, J=5.7 Hz, 2H), 2.34 (d, J=0.8 Hz, 3H). ESMS (M+1)=221.18.

B-55. (1-((6-Methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=203.25.

B-56. 5-((4-(Aminomethyl)-1H-pyrazol-1-yl)methyl)picolinonitrilehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (dd, J=2.1, 0.9Hz, 1H), 8.05 (dd, J=8.0, 0.9 Hz, 1H), 8.00 (br, 3H), 7.96 (d, J=0.8 Hz,1H), 7.85 (dd, J=8.0, 2.2 Hz, 1H), 7.59 (d, J=0.8 Hz, 1H), 5.54 (s, 2H),3.91 (q, J=5.7 Hz, 2H). ESMS (M+1)=214.16.

B-57.(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methan-d2-amineStep 1.1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile

4-cyanopyrazole (570 mg, 6.123 mmol) and5-(chloromethyl)-2-trifluoromethyl pyridine (1.257 g, 6.429 mmol) weretaken into DMF (10 mL). The mixture was stirred until reactants weredissolved. The solution was cooled to 0° C. followed by the addition ofsodium hydride (270 mg, 6.7 mmol) portion wise. The solution was stirredat room temperature for 2 hours. The reaction was quenched withsaturated NH₄Cl (10 mL). Dichloromethane (20 mL) and water (20 mL) wereadded to the reaction and the organic layer separated. The aqueous layerwas extracted twice with dichloromethane (10 mL). The combined organiclayers were washed with water (10 mL) and brine (2×10 mL), dried oversodium sulfate, filtered, and concentrated to give the crude product.The crude product was purified by column chromatography eluting with agradient of 0-30% ethyl acetate in hexane. The desired fractions wereevaporated to provide the desired product as a white solid (1.4 g, 90.7%yield). 1H NMR (300 MHz, CDCl₃) δ 8.74-8.63 (m, 1H), 7.94 (d, J=0.6 Hz,1H), 7.89 (s, 1H), 7.75 (qd, J=8.0, 1.4 Hz, 2H), 5.46 (s, 2H).

Step 2.(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methan-d2-amine

1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-4-carbonitrile(261.1 mg, 1.031 mmol), dichlorocobalt hexahydrate (54 mg, 0.2270 mmol)and di-tert-butyl dicarbonate (270.0 mg, 1.24 mmol) were taken intotrideuteriomethanol (10 ml) and cooled to 0° C. Sodium borodeuteride(130 mg, 3.1 mmol) was added to the solution in portions. The reaction,which turned black, was stirred for 2 hours. The solvent was evaporatedin vacuo to give a black residue. To the residue was addeddichloromethane (10 ml) and water (5 ml). The organic layer wascollected and filtered to remove solid suspension. The organic layer waswashed with brine, dried over MgSO4, filtered, and evaporated in vacuoto provide the desired product as white solid (255 mg, 69% yield whichwas used without further purification. 1H NMR (300 MHz, CDCl₃) δ 8.62(s, 1H), 7.68 (t, J=1.5 Hz, 2H), 7.52 (s, 1H), 7.45 (s, 1H), 6.24 (s,2H), 5.38 (s, 3H), 4.74 (s, 1H), 1.54 (s, 9H). 19F NMR (282 MHz, CDCl₃)δ −67.97.

B-58. (1-((2-Fluoropyridin-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=207.15.

B-59.(1-((4-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=257.17.

B-60.(1-((2-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=257.12.

B-61.(1-((6-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR-1H NMR (400 MHz, Methanol-d4) δ 8.00 (t,J=7.9 Hz, 1H), 7.94 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.65 (s, 1H), 7.39(d, J=7.9 Hz, 1H), 5.54 (s, 2H), 4.06 (s, 2H). ESMS (M+1)=257.12.

B-62.(1-((3-(Trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR-1H NMR (400 MHz, Methanol-d4) δ 8.91 (s,1H), 8.70 (d, J=5.2 Hz, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 6.81 (d, J=5.1Hz, 1H), 5.67 (s, 2H), 4.09 (s, 2H). ESMS (M+1)=257.21.

B-63.(1-((2-Methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=271.22.

B-64. (1-((6-Methoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.18-8.00 (m, 1H),7.83 (d, J=2.3 Hz, 1H), 7.61 (q, J=4.7, 2.9 Hz, 2H), 6.84-6.66 (m, 1H),5.30 (d, J=2.7 Hz, 2H), 4.13-3.96 (m, 2H), 3.89 (d, J=2.8 Hz, 3H). ESMS(M+1)=219.25.

B-65. (1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)methanamine

Prepared by Method C. 1H NMR (300 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.50(s, 1H), 4.45-4.30 (m, 1H), 4.10 (d, J=12 Hz, 2H), 3.80 (s, 2H),3.65-3.50 (m, 2H), 2.10-1.90 (m, 4H). ESMS (M+1)=182.61.

B-66.(1-((5-Methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.42 (d, J=2.0 Hz,1H), 8.01-7.91 (m, 4H), 7.82-7.74 (m, 1H), 7.58 (d, J=0.8 Hz, 1H), 5.48(s, 2H), 3.91 (q, J=5.6 Hz, 2H), 2.89 (s, 3H). ESMS (M+1)=271.18.

B-67. (1-((6-Chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.37 (d, J=3.1 Hz,1H), 8.02 (s, 1H), 7.90-7.77 (m, 1H), 7.77-7.64 (m, 1H), 7.52 (dt,J=8.4, 2.2 Hz, 1H), 5.48 (t, J=3.2 Hz, 2H), 4.07 (d, J=3.3 Hz, 2H). ESMS(M+1)=223.16.

B-68.(1-((5-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 8.83 (s, 1H), 8.10(dd, J=8.2, 2.3 Hz, 1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.35 (d, J=8.3 Hz,1H), 5.56 (s, 2H), 4.06 (s, 2H). ESMS (M+1)=257.21.

B-69.(1-((4-(Trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR-1H NMR (400 MHz, Methanol-d4) δ 8.77 (d,J=5.1 Hz, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 7.63 (d, J=5.1 Hz, 1H), 7.46(s, 1H), 5.57 (s, 2H), 4.06 (s, 2H). ESMS (M+1)=257.21.

B-70.(1-((5-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.95 (s, 1H), 8.80(d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.98 (s, 1H), 7.68 (d, J=2.0 Hz, 1H),5.57 (s, 2H), 4.06 (s, 2H). ESMS (M+1)=257.13.

B-71.(1-((2-(Trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz,DMSO-d6) δ3.88-3.92 (m, 2H), 5.57 (s, 2H), 3.90 (s, 2H), 7.43 (d, J=4.4Hz, 1H), 7.68 (s, 1H), 7.72 (s, 1H), 8.04 (s, 1H), 8.39 (bs, 3H), 8.74(d, J=4.8 Hz, 1H). ESMS (M+1)=256.92.

B-72.(1-((4-Methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.21 (s, 1H), 7.89(s, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 5.44 (s, 2H), 5.44 (s, 2H), 4.04(s, 5H). ESMS (M+1)=287.45.

B-73.(1-((6-(tert-Butyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.53-8.45 (m, 1H),7.95 (br, 3H), 7.90 (d, J=0.8 Hz, 1H), 7.77-7.63 (m, 1H), 7.55 (d, J=0.8Hz, 1H), 7.50 (dd, J=8.3, 0.9 Hz, 1H), 5.38 (s, 2H), 3.90 (q, J=5.7 Hz,2H), 1.30 (s, 9H). ESMS (M+1)=245.24.

B-74.(1-((5-Fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=275.19.

B-75.(1-((2-Methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.91 (s, 1H), 7.67(s, 1H), 7.53 (d, J=7.4 Hz, 1H), 7.35 (d, J=7.6 Hz, 1H), 5.42 (s, 2H),4.20-3.81 (m, 5H). ESMS (M+1)=287.36.

B-76.(1-((6-Methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.92(s, 1H), 7.87 (d, J=2.6 Hz, 1H), 7.62 (d, J=2.7 Hz, 1H), 5.36 (d, J=2.7Hz, 2H), 4.13-3.80 (m, 5H). ESMS (M+1)=287.21.

B-77.(1-((5-Methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.99(s, 1H), 7.72 (d, J=11.2 Hz, 2H), 5.65-5.43 (m, 2H), 4.12 (s, 2H), 4.02(d, J=1.6 Hz, 2H). ESMS (M+1)=287.11.

B-78. (1-((5-Fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=207.13.

B-79.(1-((6-Fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.87 (s, 1H),7.78-7.72 (m, 1H), 7.63-7.53 (m, 1H), 6.93 (d, J=1.4 Hz, 1H), 5.38 (s,2H), 3.99 (s, 2H), 2.32 (d, J=0.8 Hz, 3H). ESMS (M+1)=221.18

B-80. (1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.83 (s, 1H), 7.56(d, J=0.7 Hz, 1H), 6.95 (dd, J=9.0, 7.7 Hz, 2H), 5.40 (d, J=1.2 Hz, 2H),4.01 (s, 2H); ESMS (M+1)=242.13.

B-81.(1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride.

Step 1: (2-(Prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methanol

A mixture of (2-bromo-6-(trifluoromethyl)pyridin-3-yl)methanol (3.06 g,11.95 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.4mL), and NaHCO₃ (2.01 g, 23.93 mmol) was taken into DME (60 mL) andwater (20 mL) and purged with nitrogen for 10 minutes. Pd(dppf)Cl₂ (490mg, 0.6000 mmol) was added to the mixture then heated to reflux for 2hours. The solvent was removed in vacuo, 100 ml of ethyl acetate wasadded and washed with saturated sodium bicarbonate. The organic layerwas dried over anhydrous sodium sulfate, filtered, and evaporated toafford the crude product that was purified by column chromatography(SiO₂, 80 g) eluting with a gradient of heptane to 60% ethylacetate/heptane. The desired fractions were combined and evaporated invacuo to afford the product as a clear colorless oil (2.2 g, 85% yield).1H NMR (300 MHz, CDCl₃) δ 8.09 (d, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz,1H), 5.54-5.42 (m, 1H), 5.09 (s, 1H), 4.86 (d, J=5.4 Hz, 2H), 2.20 (d,J=1.0 Hz, 3H), 1.93 (t, J=5.6 Hz, 1H). ESI-MS m/z calc. 217.07144, found218.13 (M+1).

Step 2: 3-(Chloromethyl)-2-isopropenyl-6-(trifluoromethyl)pyridine

Thionyl chloride (1.5 ml, 20.6 mmol) was added to a solution of(2-(Prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methanol (2.2 g,10.13 mmol) in dichloromethane (18 mL) and stirred at room temperaturefor 3 h. The reaction was evaporated in vacuo to afford a yellow oil.The oil was taken into 80 ml of dichloromethane and washed with 40 ml ofsaturated sodium bicarbonate. The organic layer was dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to afford the titleproduct as a light yellow oil (2.3 g, 96% yield) that was used directlyin Step 3. 1H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.0 Hz, 1H), 7.61 (d,J=8.1 Hz, 1H), 5.59-5.47 (m, 1H), 5.28-5.16 (m, 1H), 4.74 (s, 2H),2.30-2.13 (m, 3H). ESI-MS m/z calc. 235.03757, found 236.13 (M+1)+.

Step 3: tert-Butyl((1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate

tert-Butyl ((1H-pyrazol-4-yl)methyl)carbamate (1.85 g, 9.380 mmol) and3-(chloromethyl)-2-isopropenyl-6-(trifluoromethyl)pyridine (2.30 g,9.761 mmol) was taken into anhydrous DMF (20 mL) and cooled to 0° C.Sodium hydride (434 mg, 10.85 mmol) was added to the mixture portionwiseand stirred overnight at room temperature. The reaction was quenchedwith the addition of water (80 mL) and an oil crashed out. The mixturewas extracted with ethyl acetate (2×50 ml). The organic extracts werecombined, dried over anhydrous sodium sulfate, filtered, and evaporatedin vacuo to afford the crude product. The crude product was purified bycolumn chromatography (SiO2, 80 g) eluting with a gradient of heptane to100% ethyl acetate. The desired fractions were combined and evaporatedto afford the desired product as a viscous oil that solidified to awhite solid (3.7 g, 100% yield). 1H NMR (300 MHz, CDCl₃) δ 7.57-7.48 (m,2H), 7.45 (d, J=8.1 Hz, 1H), 7.38 (s, 1H), 5.59-5.50 (m, 1H), 5.43 (s,2H), 5.08 (d, J=0.9 Hz, 1H), 4.74 (s, 1H), 4.19 (d, J=6.0 Hz, 2H),2.23-2.13 (m, 3H), 1.46 (s, 9H). ESI-MS m/z calc. 396.1773, found 397.24(M+1)+;

Step 4:(1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamine

tert-Butyl((1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate2 g, 5.04 mmol) was taken into dichloromethane (20 ml) and TFA (4 ml,3.9 mmol) and stirred at room temperature for 4 hours. The solvent wasremoved in vacuo and the residue was washed with hexanes, filtered, anddried to afford the title product (1.4 g, 90% yield). 1H NMR (300 MHz,DMSO-d6) δ 8.17 (br, 3H), 7.92 (s, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.61 (s,1H), 7.57 (d, J=8.1 Hz, 1H), 5.55 (s, 2H), 5.54 (s, 1H), 5.19 (s, 1H),3.90 (q, J=5.7 Hz, 2H), 2.09 (s, 3H). ESI-MS m/z calc. 296.12488, found297.2 (M+1)⁺

B-82.(3,5-dimethyl-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=285.21.

B-83.(1-((6-(2,2,2-Trifluoroethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

Prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J=2.4 Hz,1H), 7.93 (t, J=6.3 Hz, 3H), 7.88 (s, 1H), 7.72 (dd, J=8.5, 2.4 Hz, 1H),7.54 (s, 1H), 6.99 (d, J=8.5 Hz, 1H), 5.33 (s, 2H), 4.98 (q, J=9.1 Hz,2H), 3.89 (q, J=5.7 Hz, 2H); ESMS (M+1)=287.24

B-84.(1-((6-Fluoro-5-methoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.92 (d, J=2.4 Hz,1H), 7.77-7.60 (m, 2H), 7.62-7.49 (m, 1H), 5.42 (d, J=2.4 Hz, 2H), 4.09(s, 2H), 3.94 (t, J=2.4 Hz, 3H). ESMS (M+1)=237.50.

B-85. (1-((3,5-Dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.79 (s, 1H), 7.59(s, 1H), 5.17 (s, 2H), 4.02 (s, 2H), 3.66 (s, 1H), 2.42 (s, 3H), 2.16(s, 3H);

B-86.(1-((1,3-Dimethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ 7.99 (s, 1H), 7.87(s, 1H), 7.61 (s, 1H), 5.28 (s, 2H), 4.03 (s, 2H), 3.98 (s, 3H), 2.34(s, 3H).

B-87.(1-((3-Ethyl-5-methylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (300 MHz, CDCl₃) δ 7.42 (s, 1H), 7.22 (s,1H), 5.01 (s, 2H), 4.66 (s, 1H), 4.12 (d, J=5.5 Hz, 2H), 2.94 (s, 1H),2.87 (d, J=0.5 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.39 (s, 3H), 1.43 (s,9H), 1.18 (t, J=7.6 Hz, 3H).

B-88.(1-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.73(s, 1H), 7.61 (s, 1H), 5.31 (s, 2H), 4.02 (s, 2H), 3.92 (s, 3H). ESMS(M+1)=261.07.

B-89.(1-((1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.63(s, 1H), 6.56 (s, 1H), 5.52 (s, 2H), 4.04 (s, 2H), 3.92 (s, 3H); ESMS(M+1)=261.15.

B-90.(1-((1-Ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.84 (s, 1H), 7.61(s, 1H), 6.63 (s, 1H), 5.35 (s, 2H), 4.26 (q, J=7.2 Hz, 2H), 4.03 (s,2H), 1.43 (t, J=7.2 Hz, 3H).

B-91.(1-((1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.87 (s, 1H), 7.64(s, 1H), 6.67 (s, 1H), 5.35 (s, 2H), 4.04 (s, 2H), 3.95 (d, J=0.6 Hz,3H).

B-92. (1-((1-Ethyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.72(d, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.61 (d, J=2.1 Hz, 1H), 5.83 (s, 2H),4.33 (q, J=7.3 Hz, 2H), 4.07 (s, 2H), 1.39 (t, J=7.3 Hz, 3H); ESMS(M+1)=206.14.

B-93.(1-((5-(Trifluoromethyl)furan-2-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.90 (s, 1H), 7.64(s, 1H), 6.95 (dd, J=3.4, 1.1 Hz, 1H), 6.66-6.54 (m, 1H), 5.44 (s, 2H),4.04 (s, 2H). ESMS (M+1)=246.04.

B-94. (1-((2,5-Dimethyloxazol-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 7.89 (s, 1H), 7.65(s, 1H), 5.29 (s, 2H), 4.04 (s, 2H), 2.53 (s, 3H), 2.39 (s, 3H).

B-95 (1-(2-phenylpropyl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method A. ESMS (M+1)=216.20.

B-96. (1-(2-(4-fluorophenyl)propyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method A. ESMS (M+1)=233.13.

B-97. (1-(1-phenylpropan-2-yl)-1H-pyrazol-4-yl)methanamine hydrochloride

Prepared by Method A. ESMS (M+1)=216.24.

B-98. (1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)methanaminehydrochloride and(1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)methanamine hydrochloride.

Step 1: 1-(4-fluorobenzyl)-3-methyl-1H-pyrazole-4-carbonitrile and1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-4-carbonitrile

3-Cyano-2-methylpyrazole and 1-(bromomethyl)-4-fluorobenzene (964.0 mg,5.100 mmol) was taken into DMF (5 ml) and cooled to 0° C. Sodium hydride(240.0 mg, 6.000 mmol) was added to the reaction portionwise. Thereaction was warmed to room temperature and stirred for 12 hrs.(Observed two regioisomers by LC/MS). The reaction was quenched withsaturated NH₄Cl (10 mL) and extracted with ethyl acetate (3×20 mL). Thecombined extracts were washed with brine, dried over MgSO₄ andconcentrated to give crude mixture which was purified by columnchromatography (SiO₂) eluting with a gradient of 0-50% ethyl acetate inhexane to provide inseparable regioisomers. ESMS (M+1)=216.14.

Step 2: tert-butyl((1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)methyl)carbamate andtert-butyl((1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)methyl)carbamate

The mixture of regioisomers from Step 1(1-(4-fluorobenzyl)-3-methyl-1H-pyrazole-4-carbonitrile and1-(4-fluorobenzyl)-5-methyl-1H-pyrazole-4-carbonitrile (430.5 mg, 2.000mmol), Boc₂O (525 mg, 2.400 mmol), and dichlorocobalt hexahydrate (235.6mg, 0.99 mmol) were taken into MeOH (5 mL) and cooled to 0° C. Sodiumborohydride (940 mg, 1 mL, 24.8 mmol) was added to the mixture portionwise (the reaction turned black) and stirred for 1 hour. The reactionwas evaporated in vacuo to afford a black solid. This was suspended inethyl acetate (30 mL) and H₂O (15 mL). The organic layer was collectedand filtered to remove remaining solids. The filtrate was washed withbrine and dried over MgSO₄ to provide the crude product that waspurified by column chromatography (SiO₂) eluting with a gradient of0-50% ethyl acetate in hexane to give two peaks. The top spot was minorand the bottom spot was major. By HNMR and TLC, both spot were notseparated cleanly so combined for next step (ratio: 1:2.3).

Top spot (ratio 1:1.3): ¹H NMR (400 MHz, CDCl₃) δ 7.30 (d, J=69.7 Hz,1H), 7.18-7.00 (m, 2H), 29.9 Hz, 2H), 6.96 (td, J=8.7, 6.6 Hz, 2H), 5.14(d, J=4.53 (m, 1H), 4.92-(d, J=23.8 Hz, 3H), 4.07 (t, J=4.9 Hz, 2H),2.16 (d, J=23.8 Hz, 3H), 1.41 (d, J=3.1 Hz, 9H).

Bottom Spot (ratio 1:3): ¹NMR (400 MHz, CDCl₃) δ 7.23 (s, 1H), 7.17(ddd, J=8.1, 5.2, 2.5 Hz, 2H), 7.05-6.94 (m, 2H), 5.26-5.06 (m, 2H),4.65 (s, 1H), 4.10 (d, J=5.1 Hz, 2H), 2.28-2.09 (m, 3H), 1.44 (q, J=2.5,2.1 Hz, 10H). ESMS (M+1)=320.09.

Step 3: (1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)methanaminehydrochloride and(1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)methanamine hydrochloride

The mixture of regioisomers from Step 2 (1 g, 3.26 mmol) were taken into1,4-dioxane (2 mL). A solution of 4 M HCl (4 mL, 16 mmol) in dioxane wasadded to the solution and stirred at room temperature for 3 hours.Diethyl ether (10 mL) was added to the solution and a yellow precipitateformed. This was collected and dried to provide a mixture ofregioisomers that were not separable. ¹H NMR (400 MHz, Methanol-d4) δ8.77 (s, 1H), 8.60-8.28 (m, 1H), 8.11 (td, J=5.9, 2.8 Hz, 1H), 7.95(dddt, J=13.5, 8.7, 6.5, 2.6 Hz, 2H), 6.05 (dt, J=27.0, 2.4 Hz, 2H),4.63 (dq, J=5.2, 2.7 Hz, 2H), 4.06-3.86 (m, 2H), 3.00 (dt, J=22.3, 1.8Hz, 3H). ESMS (M+1)=220.11.

B-99.1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethan-1-amineStep 1.1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethan-1-one

Sodium hydride (60% oil dispersion; 800 mg, 20 mmol) was added to acooled (0° C.) solution of 1-(1H-pyrazol-4-yl)ethanone (2 g, 18.2 mmol)in DMF (20 ml) and stirred for 1 hour at 0° C.5-(Chloromethyl)-2-(trifluoromethyl)pyridine (3.91 g, 20 mmol) was addedto the reaction and allowed to warm to room temperature overnight. Thereaction mixture was poured into ice water and extracted with ethylacetate (3×75 ml). The combined organic extracts were dried overmagnesium sulfate, filtered, and evaporated in vacuo. The crude productwas purified by column chromatography (SiO₂) eluting with a gradient of0-5% methanol in dichloromethane. The desired fractions were evaporatedto afford the title product as a yellow solid. ESMS (M+1)=270.14.

Step 2.1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethan-1-ol

Sodium borohydride (565 mg, 14.9 mmol) was added to a solution of1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethan-1-one(4 g, 14.86 mmol) in methanol (100 ml) and stirred for 30 minutes atroom temperature. The reaction was quenched by the addition of water and1 N HCl. The organics were evaporated in vacuo, water (50 ml) added tothe solution and extracted with ethyl acetate (3×75 ml). The combinedorganic extracts were dried over magnesium sulfate, filtered, andevaporated in vacuo to afford the crude product that was purified bycolumn chromatography (SiO₂) eluting with a gradient of 0-20% methanolin dichloromethane. The desired fractions were combined to provide thetitle product as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.73-8.60 (m,1H), 7.98-7.83 (m, 2H), 7.75 (t, J=0.7 Hz, 1H), 7.41 (d, J=0.6 Hz, 1H),5.45 (s, 2H), 4.92 (d, J=4.8 Hz, 1H), 4.68 (qd, J=6.4, 4.7 Hz, 1H), 1.32(d, J=6.4 Hz, 3H). ESMS (M+1)=272.17.

Step 3.5-((4-(1-Azidoethyl)-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)pyridine

A mixture of1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethan-1-ol(3.9 g, 14.4 mmol) and diphenylphosphorylazide (5.94 g, 4.65 mmol) wastaken into anhydrous THF (55 ml) under nitrogen and cooled to 0° C. DBU(3.2 ml, 21.6 mmol) was added to the mixture and stirred at 0° C. for 2hours, then warmed to room temperature for 20 hours. The reaction wasdiluted with ethyl acetate (200 ml) and washed with water (2×50 ml) and5% HCl (10 ml). The organic layer was dried over magnesium sulfate,filtered, and evaporated in vacuo. The crude was purified by columnchromatography (SiO₂) eluting with a gradient of 10-30% ethyl acetate inhexanes. The desired fractions were combined and evaporated in vacuo toafford the title product (wt. 2.2 g, 51.6% yield) as a yellow oil thatwas used in the next step without further purification. ESMS(M+1)=297.17.

Step 4.1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethan-1-aminehydrochloride

To a solution of5-[[4-(1-azidoethyl)pyrazol-1-yl]methyl]-2-(trifluoromethyl)pyridine(2.2 g, 7.426 mmol) in dichloromethane (20 mL) was addedtriphenylphosphine (2.9 g, 11.14 mmol) and water (7 mL) and the mixturewas stirred at room temperature overnight. The reaction was notcomplete, so it was heated at 50° C. for 5 hours. The mixture wasdiluted with dichloromethane and washed with 1 N HCl (50 ml). Theaqueous layer was collected and washed with dichloromethane. The aqueouslayer was frozen and lyophilized to provide the title product, wt. 1.7 g(66.7% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.30 (s, 3H),8.02 (s, 1H), 7.92 (s, 2H), 7.65 (s, 1H), 5.53 (s, 2H), 4.58-4.24 (m,1H), 1.49 (d, J=6.8 Hz, 3H). ESMS (M+1)=271.18.

General Procedure for the Synthesis of the Intermediates in Table 1(Prepared as in Scheme F) B-101.trans-3-(3,4,5-Trifluorophenoxy)cyclobutan-1-amine hydrochloride Step 1:tert-Butyl trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)carbamate

cis-tert-Butyl N-(3-hydroxycyclobutyl)carbamate (8.06 g, 43 mmol) andtriphenylphosphine (12.42 g, 11 mL, 47.4 mmol) were taken into THE (120mL) and cooled to 0° C. Diethylazodicarboxylate (DEAD) (20.62 g, 21.6 mLof 40% w/w, 47.4 mmol) was added to the solution followed by theaddition of 3,4,5-trifluorophenol (7.01 g, 47.4 mmol). The reaction wasstirred at room temperature for 1 hour then heated at 50° C. for 1 h.The solvent was removed and the reaction was dissolved in 100 ml ofdichloromethane and washed twice with 2N sodium hydroxide. The organiclayer was evaporated and the crude product purified by columnchromatography (SiO₂) eluting with a gradient of 10-50% ethyl acetate inhexanes to provide 12.1 g (89% yield) of the desired product. 1H NMR(300 MHz, CDCl₃) δ 6.46-6.31 (m, 2H), 4.74 (d, J=10.4 Hz, 1H), 4.68 (td,J=6.9, 3.5 Hz, 1H), 4.30 (s, 1H), 2.55 (ddd, J=11.9, 8.2, 3.6 Hz, 2H),2.41 (dd, J=12.7, 6.3 Hz, 2H), 1.47 (s, 9H).

Step 2: trans-3-(3,4,5-Trifluorophenoxy)cyclobutan-1-amine hydrochloride

tert-Butyl trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)carbamate (12.18g, 38.39 mmol) was taken into 50 ml of methanol and 75 ml of a solutionof 2M HCl in diethyl ether. The solution was heated at 50° C. for 40mins. The solvent was evaporated in vacuo and the residue trituratedwith hexanes to give the product as a white solid, wt. 9.6 g (99%yield). 1H NMR (300 MHz, Methanol-d4) δ 6.72-6.53 (m, 2H), 4.97-4.89 (m,1H), 4.06-3.88 (m, 1H), 2.77-2.49 (m, 4H). ESMS (M+1)=218.17.

All compounds in Table 1 were made via the same reaction proceduredescribed above for B-101:

TABLE 1     Intermediate

    NMR     ESMS (M + 1) B-100

1H NMR (300 MHz, CD₃OD) δ 7.01 (t, J = 8.4 Hz, 2H), 6.81 (dd, J = 8.4,4.0 Hz, 2H), 4.94 (s, 1H), 3.99 (s, 1H), 2.83-2.48 (m, 4H). 181.6 B-101

1H NMR (300 MHz, CD₃OD) δ 6.72-6.53 (m, 2H), 4.97-4.89 (m, 1H),4.06-3.88 (m, 1H), 2.77- 2.49 (m, 4H). 216.37 B-102

1H NMR (300 MHz, CD₃OD) δ 7.17 (dd, J = 19.5, 9.2 Hz, 1H), 6.76 (ddd, J= 12.2, 6.6, 3.0 Hz, 1H), 6.66-6.54 (m, 1H), 4.93 (dd, J = 6.8, 4.2 Hz,1H), 3.98 (tt, J = 8.3, 6.0 Hz, 1H), 2.78-2.45 (m, 4H). 200.29 B-103

1H NMR (300 MHz, CD₃OD) δ 8.65 (d, J = 1.8 Hz, 1H), 8.52 (d, J = 2.1 Hz,1H), 8.15-8.05 (m, 1H), 5.33-5.21 (m, 1H), 4.17-3.96 (m, 1H), 2.86 (dt,J = 12.9, 6.5 Hz, 2H), 2.80-2.63 (m, 2H). 183.13 B-104

1H NMR (300 MHz, CD₃OD) δ 6.59-6.42 (m, 2H), 3.99 (dd, J = 14.1, 6.3 Hz,1H), 3.85 (s, 3H), 3.30 (d, J = 1.6 Hz, 1H), 2.73-2.53 (m, 4H). B-105

1H NMR (300 MHz, CD₃OD) □ 8.54 (d, J = 0.7 Hz, 1H), 8.33 (d, J = 0.6 Hz,1H), 5.25 (dtd, J = 86.9, 6.7, 4.0 Hz, 1H), 4.08-3.91 (m, 1H), 2.79-2.56(m, 4H). 183.18 B-106

1H NMR (300 MHz, CDCl₃) δ 8.29 (s, 3H), 7.34-7.16 (m, 1H), 6.80 (tdd, J= 9.5, 4.7, 2.6 Hz, 1H), 5.07 (s, 1H), 3.85 (s, 1H), 2.61 (dd, J = 12.7,6.1 Hz, 2H), 2.45 (dd, J = 9.0, 5.0 Hz, 2H). 218.33 B-107

1H NMR (300 MHz, DMSO-d6) δ 8.40 (s, 3H), 7.62 (td, J = 10.09, 7.8 Hz,1H), 7.15 (dt, J = 12.1, 7.9 Hz, 1H), 5.12-4.95 (m, 1H), 3.84 (s, 1H),2.75-2.57 (m, 2H), 2.49-2.34 (m, 2H). 218.33 B-108

1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 3H), 7.31 (ddd, J = 11.8, 8.9, 2.8Hz, 1H), 7.11-6.89 (m, 2H), 5.01 (t, J = 7.8 Hz, 1H), 3.93-3.76 (m, 1H),2.71-2.54 (m, 2H), 2.48-2.33 (m, 2H). 200.06 B-109

1H NMR (400 MHz CD₃OD) δ 7.41-7.28 (m, 2H), 7.14-7.01 (m, 2H), 4.16-3.86(m, 2H), 2.77-2.62 (m, 2H), 2.38 (ddd, J = 14.3, 8.0, 4.3 Hz, 2H).198.05 B-110

1H NMR (400 MHz, CD₃OD) δ 8.76 (d, J = 39.6 Hz, 1H), 8.70 (s, 1H), 8.11(s, 1H), 5.26 (s, 1H), 4.14-3.97 (m, 1H), 2.88-2.56 (m, 4H). 233.03B-111

1H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz,2H), 4.23 (tt, J = 8.3, 4.1 Hz, 1H), 4.05 (p, J = 7.5 Hz, 1H), 2.84(ddd, J = 12.3, 8.6, 4.3 Hz, 2H), 2.44 (ddd, J = 14.5, 7.9, 3.9 Hz, 2H).247.97 B-112

1H NMR (400 MHz, CD₃OD) δ 8.30 (d, J = 2.5 Hz, 1H), 7.76 (d, J = 8.7 Hz,1H), 7.42 (dd, J = 19.3, 12.4 Hz, 1H), 5.14 (s, 1H), 4.11-3.98 (m, 1H),2.71 (tdd, J = 14.1, 11.0, 4.8 Hz, 4H). 233.03 B-113

1H NMR (400 MHz, CD₃OD) δ 7.20 (d, J = 9.0 Hz, 2H), 6.92-6.86 (m, 2H),5.02-4.91 (m, 1H), 4.06-3.90 (m, 1H), 2.78-2.55 (m, 4H). 248.02 B-114

1H NMR (400 MHz, CD₃OD) δ 7.11-6.95 (m, 2H), 4.82 (s, 5H), 4.15-4.04 (m,1H), 4.00 (dd, J = 15.0, 7.4 Hz, 1H), 2.83-2.66 (m, 2H), 2.45-2.32 (m,2H). 234.1 B-115

1H NMR (300 MHz, CD₃OD) δ 8.54 (s, 2H), 5.16 (d, J = 25.9 Hz, 1H), 4.05(s, 1H), 2.74 (s, 4H). 234.12 B-116

1H NMR (400 MHz, CD₃OD) δ 8.70 (d, J = 5.4 Hz, 1H), 8.51 (s, 1H), 7.54(s, 1H), 7.38 (d, J = 4.3 Hz, 1H), 5.38 (s, 1H), 4.12 (s, 1H), 3.02-2.84(m, 2H), 2.84-2.66 (m, 2H) 233.13 B-117

178.16 B-118

232.13 B-119

194.04 B-120

1H NMR (400 MHz, CD₃OD) δ 6.86-6.72 (m, 2H), 6.58 (td, J = 8.5, 2.9 Hz,1H), 4.99-4.89 (m, 1H), 4.07-3.93 (m, 1H), 3.83 (s, 3H), 3.03-2.24 (m,4H). 212.1 B-121

1H NMR (400 MHz, CD₃OD) δ 7.70 (d, J = 3.0 Hz, 1H), 7.33 (dd, J = 9.0,3.0 Hz, 1H), 6.87 (dd, J = 9.0, 0.5 Hz, 1H), 5.02-4.90 (m, 1H), 4.77 (t,J = 8.8 Hz, 2H), 4.08-3.88 (m, 1H), 2.69-2.52 (m, 4H) 263.11 B-122

224.17 B-123

212.15 B-124

183.11 B-125

266.12 B-126

1H NMR (400 MHz, CD₃OD) δ 7.83 (d, J = 2.9 Hz, 1H), 7.49 (dd, J = 8.9,2.9 Hz, 1H), 7.31 (t, J = 73.2 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H),5.12-5.06 (m, 1H), 4.08-3.93 (m, 1H), 2.85-2.69 (m, 2H), 2.69-2.55 (m,2H). 231.14 B-127

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General Procedure for the Synthesis of the Intermediates in Table 2(Scheme G)

The compounds were prepared in 2 steps by (1) reaction oftrans-tert-Butyl N-(3-hydroxycyclobutyl)carbamate and aphenylthiol,phenol, or pyrazole derivative, followed by (2) deprotection to providethe intermediate using the procedures described for scheme F (seeprocedure for B-101).

TABLE 2     Intermediate

    NMR     ESMS (M + 1) B-128

1H NMR (300 MHz, CD₃OD) δ 7.06-6.95 (m, 2H), 6.89-6.78 (m, 2H), 4.54 (p,J = 6.9 Hz, 1H), 3.63-3.47 (m, 1H), 182.12 3.04-2.86 (m, 2H), 2.25(dddd, J = 10.1, 8.6, 6.1, 2.5 Hz, 2H). B-129

1H NMR (300 MHz, CD₃OD) δ 6.73-6.59 (m, 2H), 4.57 (p, J = 6.9 Hz, 1H),3.56 (p, J = 8.0 Hz, 1H), 2.99 (dtd, J = 10.0, 7.1, 3.0 Hz, 2H),2.34-2.18 (m, 2H). 218.17 B-130

1H NMR (300 MHz, CD₃OD) δ 7.48-7.32 (m, 2H), 7.14-7.01 (m, 2H),3.85-3.49 (m, 2H), 198.1 2.93-2.74 (m, 2H), 2.31- 2.08 (m, 2H). B-131

1H NMR (400 MHz, CD₃OD) δ 7.58 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.3 Hz,2H), 3.86 (ddq, 248.02 J = 25.0, 8.7, 7.6 Hz, 2H), 3.05-2.89 (m, 2H),2.33-2.14 (m, 2H). B-132

1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 3H), 7.32-7.18 (m, 2H), 3.79 (tt, J= 9.4, 7.4 Hz, 1H), 3.68-3.51 (m, 1H), 2.78 (dtd, J = 10.3, 7.4, 2.9 Hz,2H), 2.24-2.10 (m, 2H). 234.12 B-133

1H NMR (400 MHz, CD₃OD) δ 7.42-7.33 (m, 2H), 7.23 (dd, J = 8.8, 0.8 Hz,2H), 3.89- 264.1 3.67 (m, 2H), 2.99-2.82 (m, 2H), 2.27-2.09 (m, 2H).

The following intermediates in Table 3 were prepared in 2 steps by (1)reaction of cis-tert-butyl (N-(3-(hydroxymethyl)cyclobutyl)carbamate anda phenol, thiophenol, or pyrazole derivative followed by (2)deprotection to provide the desired intermediate using the proceduresdescribed for intermediate B-101.

TABLE 3 Inter- ESMS mediate L-Ring A NMR (M + 1) B-134

1H NMR (300 MHz, CD₃OD) δ 6.81-6.63 (m, 2H), 3.96 (d, J = 5.4 Hz, 2H),3.83-3.65 (m, 1H), 2.72-2.57 (m, 1H), 2.56- 2.42 (m, 2H), 2.25- 2.03 (m,2H). 232.17 B-135

1H NMR (300 MHz, CD₃OD) δ 7.08-6.85 (m, 4H), 3.95 (d, J = 5.4 Hz, 2H),3.73 (p, J = 8.2 Hz, 1H), 2.72-2.58 (m, 1H), 196.19 2.57-2.40 (m, 2H),2.19- 1.99 (m,2H). B-136

1H NMR (300 MHz, CD₃OD) δ 8.63 (s, 2H), 8.24 (d, J = 9.9 Hz, 1H), 4.31(d, J = 4.9 Hz, 1H), 4.14 (dt, J = 6.9, 4.1 Hz, 197.18 1H), 3.86-3.77(m, 1H), 2.75 (s, 1H), 2.64-2.47 (m, 2H), 2.34-2.17 (m, 2H). B-137

1H NMR (300 MHz, CD₃OD) δ 7.86 (d, J = 1.4 Hz, 1H), 7.59 (ddd, J = 9.4,6.6, 3.4 Hz, 1H), 7.08-6.93 (m, 1H), 4.28- 197.18 4.10 (m, 1H), 4.01(dd, J = 23.5, 6.5 Hz, 2H), 3.84-3.65 (m, 1H), 2.74- 2.33 (m, 3H), 2.24-2.04 (m, 2H). B-138

1H NMR (300 MHz, CD₃OD) δ 7.25-7.07 (m, 1H), 6.88 (ddd, J = 12.4, 6.7,3.0 Hz, 1H), 6.73 (ddd, J = 9.0, 4.0, 2.5 Hz, 1H), 3.95 (d, J = 5.4 Hz,2H), 3.82-3.64 (m, 1H), 2.72-2.43 (m, 3H), 2.09 (ddd, J = 18.8, 9.3, 2.6Hz, 2H). B-139

1H NMR (300 MHz, CD₃OD) δ 7.77 (s, 1H), 6.59 (s, 1H), 4.29 (d, J = 7.1Hz, 2H), 3.68 (p, J = 8.2 Hz, 1H), 2.79-2.55 (m, 1H), 2.53-2.37 (m, 2H),1.99 (ddd, J = 19.0, 220.2  9.5, 2.7 Hz,2H). B-140

1H NMR (300 MHz, CD₃OD) δ 7.43 (ddd, J = 19.1, 8.0, 3.1 Hz, 2H), 7.20(dd, J = 9.2, 4.1 Hz, 1H), 4.12 (d, J = 5.8 Hz, 221.19 2H), 3.74 (td, J= 16.4, 8.2 Hz, 1H),2.80-2.63 (m, 1H), 2.55 (dtd, J = 10.5, 7.6, 2.7 Hz,2H), 2.11 (ddd, J = 18.8, 9.3, 2.6 Hz, 2H).

B-141. trans-3-(3,4,5-Trifluorophenoxy)cyclopentan-1-amine Step 1:tert-Butyl ((trans)-3-(3,4,5-trifluorophenoxy)cyclopentyl)carbamate

A mixture of tert-butyl (cis-3-hydroxycyclopentyl)carbamate (63.5 g,315.5 mmol), triphenylphosphine (107.6 g, 410.2 mmol) and3,4,5-trifluorophenol (60.74 g, 410.2 mmol) in THE (750 mL) was cooleddown to 0° C. Diisopropyl azodicarboxylate (82 mL, 410.2 mmol) was addeddropwise, maintaining the reaction temperature below 10° C. The reactionwas slowly warmed to room temperature and stirred overnight. The solventwas evaporated in vacuo, the residue was dissolved in 2 L ofdichloromethane and washed with 1 N NaOH (2×1 L); the organic layer wasdried over Na2SO4, filtered, and evaporated. The residue was dissolvedin dichloromethane and eluted through a 1.5 L plug of silica gel. Thefiltrate was evaporated in vacuo and purified through a 1 L plug ofsilica gel eluting with dichloromethane. The first 2 L of the filtratewas concentrated to provide the product (90 g, 86% yield) as whitesolid. 1H NMR (300 MHz, CDCl₃) δ 6.49-6.38 (m, 2H), 4.69 (ddd, J=8.4,5.8, 2.5 Hz, 1H), 4.49 (s, 1H), 4.18 (d, J=6.9 Hz, 1H), 2.37-2.06 (m,3H), 1.82 (dddd, J=20.4, 14.1, 9.1, 7.6 Hz, 2H), 1.47 (d, J=6.1 Hz, 9H).

Step 2: trans-3-(3,4,5-Trifluorophenoxy)cyclopentan-1-aminehydrochloride

A 4M solution of HCl in dioxane (100 ml, 400 mmol) was added to asolution of tert-Butyl((trans)-3-(3,4,5-trifluorophenoxy)cyclopentyl)carbamate (13.5 g, 40.7mmol) in dioxane (80 ml). The reaction was stirred at room temperaturefor 18 hours. Diethyl ether was added to the residue and stirred at roomtemperature. The white solid was collected by vacuum filtration, washedwith diethyl ether, and dried in an oven to provide the title product,10.3 g (95% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 3H), 7.08-6.83(m, 2H), 5.06-4.86 (m, 1H), 3.74-3.58 (m, 1H), 2.35-1.90 m 4H),1.85-1.53 (m, 2H).

B-142. trans-3-(6-Trifluoromethyl pyridin-3-yl oxy cyclopentan-1-amine

The compound was prepared in the same manner as intermediate B-141 toprovide the title compound as a diastereomeric pair of trans isomers.ESMS (M+1)=247.13.

B-143. cis-3-(3,4,5-Trifluorophenoxy)cyclopentan-1-amine hydrochloride

The compound was prepared in the same manner as the procedure reportedfor intermediate B-142 to provide the title compound (82% yield) as amixture of cis-diastereomers. 1H NMR (300 MHz, CDCl₃) δ 6.53-6.41 (m,2H), 4.77 (s, 1H), 4.66 (ddd, J=8.1, 5.3, 2.5 Hz, 1H), 4.14 (s, 1H),2.41-2.24 (m, 1H), 2.17-2.02 (m, 1H), 2.02-1.90 (m, 2H), 1.85-1.64 (m,2H), 1.46 (s, 9H);

B-144. (6-((4-fluorobenzyl)oxy)pyridin-3-yl)methanamine hydrochlorideStep 1: 6-((4-fluorobenzyl)oxy)nicotinonitrile

Sodium hydride (60% oil dispersion; 640 mg, 16 mmol) was added to acooled solution (0° C.) of (4-fluorophenyl)methanol (1.9 g, 15 mmol) inDMF (20 ml). After stirring for 30 minutes, 6-chloronicotinonitrile (2.6g, 19 mmol) was added to the mixture and the reaction was warmed to roomtemperature and stirred for 14 hours. The mixture was poured into asaturated ammonium chloride solution and a grey precipitate formed. Theprecipitate was collected by vacuum filtration and washed well withwater. The collected filter cake was dried in a vacuum oven at 50° C.for 16 hours to provide the title product, wt. 1.6 g. 1H NMR (400 MHz,CDCl₃) δ 8.37 (dd, J=2.3, 0.8 Hz, 1H), 7.66 (dt, J=8.7, 1.6 Hz, 1H),7.34-7.23 (m, 2H), 6.94 (t, J=8.7 Hz, 2H), 6.73 (dd, J=8.6, 0.8 Hz, 1H),5.26 (s, 2H); ESMS (M+1)=228.8.

Step 2: tert-Butyl((6-((4-fluorobenzyl)oxy)pyridin-3-yl)methyl)carbamate

6-((4-fluorobenzyl)oxy)nicotinonitrile (1.23 g, 5.23 mmol), Boc₂O (1.37g, 6.27 mmol), and dichlorocobalt hexahydrate (249 mg, 1.046 mmol) weretaken into methanol (20 ml) and cooled to 0° C. Sodium borohydride (980mg, 1.047 mmol) was added to the mixture portion wise and stirred for 1hour. The solvent was evaporated in vacuo to afford a black residue.This was taken into ethyl acetate and water. The organic layer wascollected and filtered to remove the fine solid, then washed with brineand dried over anhydrous sodium sulfate, filtered, and evaporated invacuo to provide the title product, wt. 1.6 g (82.9% yield). 1H NMR (400MHz, CDCl₃) δ 8.08 (d, J=2.4 Hz, 1H), 7.57 (dd, J=8.5, 2.4 Hz, 1H), 7.44(dd, J=8.5, 5.4 Hz, 2H), 7.07 (t, J=8.7 Hz, 2H), 6.78 (d, J=8.5 Hz, 1H),5.34 (s, 2H), 4.82 (s, 1H), 4.26 (d, J=6.0 Hz, 2H), 1.47 (s, 9H); ESMS(M+1)=333.15.

Step 3: (6-((4-fluorobenzyl)oxy)pyridin-3-yl)methanamine hydrochloride

tert-Butyl ((6-((4-fluorobenzyl)oxy)pyridin-3-yl)methyl)carbamate (1.6g, 4.81 mmol) was dissolved in 10 ml of dioxane. A 4M solution of HCl indioxane (6 ml, 24 mmol) was added to the solution and stirred at roomtemperature for 1 hour (a precipitate formed 10 minutes after addition).The solvent was evaporated to provide a residue that was triturated withdiethyl ether and stirred for 1 hour resulting in a white precipitate.The solid was collected by vacuum filtration, washed with diethyl ether,and dried under vacuum to provide the title product, wt. 1.28 g(quantitative yield). 1H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J=24.6Hz, 1H), 8.09 (s, 1H), 7.59-7.40 (m, 2H), 7.20 (d, J=8.5 Hz, 1H),7.16-6.98 (m, 2H), 5.42 (d, J=15.3 Hz, 2H), 4.15 (d, J=16.2 Hz, 2H);ESMS (M+1)=233.03.

B-145.(6-((1-(4-Fluorophenyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)methanamine Step1: 1-(4-fluorophenyl)pyrrolidin-3-ol

Sodium borohydride (535 mg, 14.1 mmol) was added to a cooled solution(0° C.) of 1-(4-fluorophenyl)pyrrolidin-3-one (1.94 g, 10.83 mmol) inMeOH (12 mL) and stirred for 3 hours. After warming to room temperature,the reaction was quenched by the addition of water and saturated sodiumbicarbonate followed by extraction with ethyl acetate (3×75 ml). Thecombined organic extracts were washed with brine, dried over sodiumsulfate, filtered, and evaporated in vacuo. The resulting residue wastriturated with diethyl ether to obtain the product as a solid, wt. 1.86g (81% yield). ESMS (M+1)=181.92.

Step 2: 6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)nicotinonitrile

Sodium hydride (97 mg, 2.21 mmol) was added to a solution of1-(4-fluorophenyl)pyrrolidin-3-ol (400 mg, 2.43 mmol) in DMF (4 ml) andstirred at room temperature. 6-Fluoronicotinonitrile (295 mg, 2.43 mmol)was added to the reaction and stirred at room temperature overnight.Water (75 ml) was added to the reaction and extracted with ethyl acetate(3×75 ml). The combined extracts were washed with brine, dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo. The crudeproduct was purified by column chromatography (SiO₂) eluting with agradient of 0-10% methanol (0.1% ammonia) in dichloromethane.Evaporation of the desired fractions afforded 410 mg (62% yield) of thetitle compound. ESMS (M+1)=284.55.

Step 3:(6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)methanamine

A mixture of 6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)nicotinonitrile(410 mg, 1.45 mmol) and nickel were taken into 7 N ammonia in methanol(20 ml) and hydrogenated at 3 bar overnight. The reaction was filteredand evaporated in vacuo to afford the title compound, 405 mg (82.8%yield); ESMS (M+1)=285.16.

B-146. (6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methanamineStep 1: 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile

Sodium hydride (310 mg, 7.77 mmol) was added to a solution of4-(trifluoromethyl)-1H-pyrazole (877 mg, 6.45 mmol) in anhydrous DMF (5mL). After 10 minutes, 4-(trifluoromethyl)-1H-pyrazole (877 mg, 6.45mmol) was added to the mixture and heated to 80° C. for 1 hour. Thereaction was cooled to room temperature and poured into water (125 ml)resulting in the formation of a precipitate. The precipitate wasfiltered, washed with water, and dried under vacuum to provide the titleproduct, wt. 1.44 g (88% yield). ESMS (M+1)=239.3.

Step 2: (6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methanamine

A mixture of 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile(1.26 g, 5.27 mmol) and nickel (˜300 mg) in 7N ammonia in methanol (25ml) was hydrogenated at 3 bar overnight. The mixture was filtered andthe filtrate concentrated to afford the title product, wt. 1.26 g (83%yield). The product was used without further purification. ESMS(M+1)=243.35.

B-147.(6-((1-(4-Fluorophenyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)methanamine Step1: 1-(4-fluorophenyl)pyrrolidin-3-ol

Sodium borohydride (535 mg, 14.1 mmol) was added to a cooled solution(0° C.) of 1-(4-fluorophenyl)pyrrolidin-3-one (1.94 g, 10.83 mmol) inMeOH (12 mL) and stirred for 3 hours. After warming to room temperature,the reaction was quenched by the addition of water and saturated sodiumbicarbonate and extracted with ethyl acetate (3×75 ml). The organicextracts were combined, washed with brine, dried over sodium sulfate,filtered, and evaporated in vacuo. The residue was triturated withdiethyl ether to obtain the product as a solid, wt. 1.86 g (81% yield).ESMS (M+1)=181.92.

Step 2: 6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)nicotinonitrile

Sodium hydride (97 mg, 2.21 mmol) was added to a solution of1-(4-fluorophenyl)pyrrolidin-3-ol (400 mg, 2.43 mmol) in DMF (4 ml) andstirred at room temperature. 6-Fluoronicotinonitrile (295 mg, 2.43 mmol)was added to the reaction and stirred at room temperature overnight.Water (75 ml) was added to the reaction followed by extraction withethyl acetate (3×75 ml). The combined extracts were washed with brine,dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo.The crude product was purified by column chromatography (SiO2) elutingwith a gradient of 0-10% methanol (0.1% ammonia) in dichloromethane.Evaporation of the desired fractions afforded 410 mg (62% yield) of thetitle compound. ESMS (M+1)=284.55.

Step 3:(6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)methanamine

A mixture of 6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)nicotinonitrile(410 mg, 1.45 mmol) and nickel were taken into 7 N ammonia in methanol(20 ml) and hydrogenated at 3 bar overnight. The reaction was filteredand evaporated in vacuo to afford the title compound, 405 mg (82.8%yield); ESMS (M+1)=285.16.

B-148. (6-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methanamineStep 1. 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile

Sodium hydride (310 mg, 7.8 mmol) was added to a solution of4-(trifluoromethyl)-1H-pyrazole (877 mg, 6.45 mmol) in DMF (5 mL) andstirred at room temperature for 10 minutes.6-Fluoropyridine-3-carbonitrile (730 mg, 6 mmol) was added to themixture then at 80° C. for 1 hour. The reaction was cooled to roomtemperature then poured into water (125 ml). The precipitate wascollected by vacuum filtration and washed well with water to provide thetitle product, wt. 1.4 g. ESMS (M+1)=239.3.

Step 2. (6-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methanamine

Approximately, 300 mg of nickel (washed with methanol) was added to asolution of 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)nicotinonitrile in 25ml of 7 N NH3 in methanol. And hydrogenated (3 bar) overnight. Thereaction was filtered through Celite and concentrated in vacuo to affordthe title product. ESMS (M+1)=243.35.

B-149.5-(Aminomethyl)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-2-amine.

Step 1.6-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)nicotinonitrile

A mixture of 6-fluoropyridine-3-carbonitrile (680 mg, 5.569 mmol),1-(2,2,2-trifluoroethyl)pyrazol-4-amine (895 mg, 5.420 mmol), andpotassium carbonate (1.74 g, 12.6 mmol) were taken into 10 ml of DMF andmicrowaved for 30 minutes at 160 C. The reaction was poured into waterand extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with water (2×20 mL) and brine (1×20 mL), and driedover anhydrous sodium sulfate and concentrated in vacuo to provide thetitle product, wt. 1.4 g; ESMS (M+1)=268.01.

Step 2.5-(Aminomethyl)-N-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridin-2-amine

To a mixture of methanol washed Nickel (about 0.3 g) in methanol (50 mL)was added6-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)nicotinonitrile(1,600 mg, 5.988 mmol) and 7N NH3 in M methanol (20 ml). The mixture washydrogenated at 3 bar for 18 hours. The nickel was magneticallyretrieved and the reaction filtered through Celite. The filtrate wasevaporated in vacuo to afford the title product that was used withoutfurther purification, wt. 1.2 g; ESMS (M+1)=272.15.

B-150.(1-(1-(6-(Trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)methanamine

Prepared by Method A. ESMS (M+1)=271.13.

B-151. (1-((5-Fluoropyrimidin-2-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. 1H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=0.8 Hz,2H), 8.08-8.03 (m, 1H), 7.78-7.73 (m, 1H), 5.65 (d, J=1.1 Hz, 2H), 4.10(s, 2H). ESMS (M+1)=208.18.

B-152. (1-((2-Methylpyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

Prepared by Method B. ESMS (M+1)=208.18.

B-153.(1-(5-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

Step A: tert-Butyl((1-(5-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)carbamate

tert-Butyl ((1H-pyrazol-4-yl)methyl)carbamate (320 mg, 1.62 mmol) and5-(chloromethyl)-2-(trifluoromethyl)pyrimidine (318 mg, 1.62 mmol) weretaken into 6 ml of anhydrous DMF and cooled to 0° C. Sodium hydride (60%oil dispersion w/w; 85 mg, 2.12 mmol) was added to the solution. Thereaction was warmed to room temperature and stirred for 16 hours. Waterwas added to the reaction and a precipitate formed. The precipitate wascollected by vacuum filtration and washed well with water. The crudeproduct was purified column chromatography (SiO₂) eluting with 0-100%ethyl acetate in heptane. The desired fractions were combined andevaporated to afford the title product, wt. 150 mg (24% yield). 1H NMR(300 MHz, CDCl₃) δ 8.73 (s, 1H), 8.62 (s, 1H), 7.80 (s, 1H), 4.85 (s,1H), 4.30 (d, J=5.9 Hz, 2H), 2.79 (s, 3H), 1.50 (s, 9H); ESMS(M+1)=358.23.

Step B:(1-(5-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

tert-Butyl((1-(5-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)carbamate(142 mg, 0.397 mmol) was taken into 5 ml of 4M HCl in dioxane (20 mmol)and stirred at room temperature for 2 hours. The resulting precipitatewas collected by vacuum filtration, washed well with diethyl ether, anddried under vacuum to provide the title product, wt. 130 mg (99% yield).1H NMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.87 (s, 1H), 7.98 (s,1H), 4.17 (s, 2H), 2.77 (s, 3H).

B-154.N-methyl-1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid salt Step 1: tert-butylmethyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate

Sodium hydride (60% oil dispersion w/w; 675 mg, 16.84 mmol) was added toa cooled (0° C.) solution of tert-butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(4 g, 11.23 mmol) in DMF (100 ml) and stirred under nitrogen for 30minutes. Iodomethane (0.91 ml, 14.6 mmol) was added to the mixture. Thereaction was warmed to room temperature and stirred for 2 hours. Thesolution was poured onto ice water (100 ml) and extracted with ethylacetate (2×100 ml). The combined extracts were washed with saturatedsodium bicarbonate and brine, dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford the crude product. Theproduct was purified by column chromatography (SiO₂, 80 g) eluting witha gradient of 0-20% methanol in dichloromethane. The desired fractionswere collected and evaporated in vacuo to afford the title product, wt 3g (72.1% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.94-7.83 (m,2H), 7.81 (s, 1H), 7.42 (s, 1H), 5.49 (s, 2H), 4.18 (s, 2H), 2.89 (s,3H), 1.39 (s, 9H). ESMS (M+1)=371.17.

Step 2:N-methyl-1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoro acetic acid salt

Trifluoroacetic acid (4.2 ml, 54 mmol) was to a solution of tert-Butylmethyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(2 g, 5.4 mmol) in 15 ml of dichloromethane and stirred at roomtemperature for 2 hours. The solvent was removed in vacuo to afford aresidue that was dried under vacuum at 50° C. for 18 hours to afford thetitle product, wt. 2.4 g (89.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.66(br, 3H), 8.00 (d, J=0.8 Hz, 1H), 7.91 (d, J=1.5 Hz, 2H), 7.61 (d, J=0.8Hz, 1H), 5.55 (s, 2H), 4.01 (t, J=5.6 Hz, 2H), 2.54 (t, J=5.4 Hz, 3H).ESMS (M+1)=271.18.

B-155. trans-3-((5-fluoropyrimidin-2-yl)oxy)cyclobutan-1-aminehydrochloride Step 1: tert-butyl(trans-3-((5-fluoropyrimidin-2-yl)oxy)cyclobutyl)carbamate

Sodium hydride (480 mg, 12 mmol) was added to a solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (2.04 g, 10.9 mmol) and2-chloro-5-fluoropyrimidine (1.45 g, 10.9 mmol) in 10 ml of anhydrousDMF at room temperature for 18 hours. Reaction was not complete, so thereaction was heated at 90° C. for 24 hours. The reaction was cooled toroom temperature then poured into water (100 ml) and extracted withethyl acetate (3×100 ml). The combined extracts were washed with water(2×50 ml) and brine (50 ml), dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo. The crude product was purified bycolumn chromatography (SiO₂) eluting with a gradient of 0-100% ethylacetate in hexanes. The desired fractions were evaporated in vacuo toafford the title product, wt. 1.71 g (55% yield). 1H NMR (300 MHz,CDCl₃) δ 8.37 (s, 1H), 8.18 (d, J=1.0 Hz, 1H), 5.26 (dt, J=7.3, 2.9 Hz,1H), 4.86 (dt, J=6.8, 3.2 Hz, 1H), 4.38-4.27 (m, 1H), 2.67-2.39 (m, 4H),1.46 (s, 9H).

Step 2: trans-3-((5-fluoropyrimidin-2-yl)oxy)cyclobutan-1-aminehydrochloride

4M HCl (50 ml, 200 mmol) in dioxane was added to a solution oftert-butyl (trans-3-((5-fluoropyrimidin-2-yl)oxy)cyclobutyl)carbamate in50 ml of dioxane and stirred at room temperature for 2 hours. Aprecipitate formed that was collected by vacuum filtration and washedwith diethyl ether and hexanes to afford the title product, wt. 1.3 g(98% yield). 1H NMR (300 MHz, Methanol-d4) δ 8.54 (d, J=0.7 Hz, 1H),8.33 (d, J=0.6 Hz, 1H), 5.25 (dtd, J=86.9, 6.7, 4.0 Hz, 1H), 4.08-3.91(m, 1H), 2.79-2.56 (m, 4H).

B-156: trans-4-(4-fluorophenoxy)tetrahydrofuran-3-amine Step 1:tert-butyl (trans-4-(4-fluorophenoxy)tetrahydrofuran-3-yl)carbamate

tert-butyl (cis-4-hydroxytetrahydrofuran-3-yl)carbamate (600 mg, 2.95mmol), 4-fluorophenol (496 mg, 4.43 mmol), and triphenylphosphine (1.16g, 4.43 mmol) were dissolved into 5 ml of anhydrous THE and cooled to 0°C. diisopropyl azodicarboxylate (0.9 ml, 4.43 mmol) was added to themixture dropwise. The reaction was warmed to room temperature andstirred for 18 hours. The solvent was removed in vacuo to afford thecrude product that was purified by column chromatography (SiO₂) elutingwith a gradient of 0-100% ethyl acetate in heptane to afford the titleproduct, wt. 375 mg (43% yield). ESMS (M+1)=298.39.

Step 2: trans-4-(4-fluorophenoxy)tetrahydrofuran-3-amine

Trifluoro acetic acid (1 ml, 12.8 mmol) was added to a solution oftert-butyl (trans-4-(4-fluorophenoxy)tetrahydrofuran-3-yl)carbamate (375mg, 1.26 mmol) in 2 ml of dichloromethane and stirred at roomtemperature for 16 hours. The reaction was evaporated in vacuo and theresidue dissolved in saturated sodium bicarbonate (10 ml) and extractedwith dichloromethane (2×10 ml). The combined extracts were dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo to affordthe title product as a clear yellow oil, wt. 234 mg (94% yield); ESMS(M+1)=198.07.

B-157: cis-3-(((4-fluorobenzyl)oxy)methyl)cyclobutan-1-aminehydrochloride Step 1: tert-butyl(cis-3-(((4-fluorobenzyl)oxy)methyl)cyclobutyl)carbamate

Sodium hydride (220 mg, 5.47 mmol) was added to a solution of tert-butyl((cis-3-(hydroxymethyl)cyclobutyl)carbamate (1 g, 4.97 mmol) and4-fluorobenzyl bromide (940 mg, 5.47 mmol) in THE (10 ml) at 0° C. Thereaction was warmed to room temperature and stirred for 16 hours. Water(50 ml) was added to the reaction followed by extraction with ethylacetate (3×100 ml). The combined extracts were washed with water (2×50ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered,and evaporated in vacuo to afford the title product, 1.3 g (98% yield).ESMS (M+1)=310.14.

Step 2: cis-3-(((4-fluorobenzyl)oxy)methyl)cyclobutan-1-aminehydrochloride

tert-butyl (cis-3-(((4-fluorobenzyl)oxy)methyl)cyclobutyl)carbamate (1.3g, 4.2 mmol) was taken into 4M HCl in dioxane (50 ml) and stirred atroom temperature for 2 hours. The reaction was evaporated in vacuo toafford the crude product that purified by reverse MPLC (C18 column)eluting with 10-100% Acetonitrile in water (0.1% TFA). The desiredfractions were evaporated in vacuo to afford the desired product thatwas dissolved in dichloromethane and precipitated by the addition ofdiethyl ether. The precipitate was collected by vacuum filtration,washed with diethyl ether and hexanes, and dried under vacuum at 50° C.to afford the title product, wt. 600 mg (58% yield). ESMS (M+1)=210.47.

B-158: trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclopentan-1-aminehydrochloride

The compound was prepared in a similar manner as reported for procedureB-141 via reaction of cis-tert-butyl(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclopentyl)carbamate and3-(trifluoromethyl)-1H-pyrazole followed by deprotection to afford thetitle product. ESMS (M+1)=220.11.

B-159: cis-N-(3-aminocyclopentyl)-3,4,5-trifluorobenzamide Step 1:tert-butyl cis-(3-(3,4,5-trifluorobenzamido)cyclopentyl)carbamate

3,4,5-Trifluorobenzoyl chloride (70 μl, 0.38 mmol) was added to amixture of tert-butyl cis-N-(3-aminocyclopentyl)carbamate (70 mg, 0.345mmol) in dichloromethane (1.5 ml) and triethylamine (60 μl, 0.41 mmol).The mixture was stirred at room temperature for 16 hours. The reactionwas quenched with saturated sodium bicarbonate and extracted withdichloromethane. The organic layer was evaporated in vacuo to afford thecrude product. The product was purified by column chromatography elutingwith a gradient of 0-100% ethyl acetate in heptane to afford the titleproduct, wt. 92 mg (74% yield). ESMS (M+1)=359.13.

Step 2: cis-N-(3-aminocyclopentyl)-3,4,5-trifluorobenzamide

tert-butyl cis-(3-(3,4,5-trifluorobenzamido)cyclopentyl)carbamate (92mg, 0.26 mmol) was dissolved in dichloromethane (1 ml) and TFA (0.2 ml,2.6 mmol) and stirred at room temperature for 16 hours. The reaction wasevaporated in vacuo to afford the title product as a TFA salt, wt. 95mg. ESMS (M+1)=259.10.

B-160(R)-(1-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methanaminedihydrochloride Step 1: Benzyl(R)-3-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

Sodium hydride (125 mg, 3.125 mmol) was added to a solution oftert-butyl N-(1H-pyrazol-4-ylmethyl)carbamate (454 mg, 2.302 mmol) inDMF (5 mL) and stirred for 10 minutes. Benzyl(3S)-3-(p-tolylsulfonyloxy)pyrrolidine-1-carboxylate (1.04 g, 2.76 mmol)was added to the mixture and stirred for 18 hours. The reaction wasdiluted with EtOAc (100 ml) and washed with water (50 ml), saturatedNaHCO₃(50 ml), and brine (50 ml). The organic layer was dried oversodium sulfate, filtered, and evaporated in vacuo. The crude product waspurified by column chromatography (SiO₂) eluting with 10% methanol indichloromethane to provide 2.76 g (55% yield) of the title compound. ¹HNMR (300 MHz, CD₃OD) δ 7.60-7.17 (m, 7H), 6.86 (s, 1H), 5.45 (s, 1H),5.09 (s, 2H) 4.97-4.76 (m, 2H), 4.06 (d, J=4.1 Hz, 2H), 3.90-3.40 (m,4H), 2.43-2.20 (m, 2H), 1.41 (s, 9H).

Step 2: tert-Butyl(R)-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate

To a slurry of 10% Pd/C (50 mg) in methanol (25 mL) was added benzyl(3R)-3-(4-(((tert-butoxycarbonyl)amino)methyl)pyrazol-1-yl)pyrrolidine-1-carboxylate(483 mg, 1.21 mmol) and the resulting slurry stirred under a hydrogenballoon for 14 hours. The mixture was filtered, washed with methanol,and concentrated in vacuo to provide 261 mg (81% yield) of the crudeproduct. ESMS (M+1)=267.38 (M+1).

Step 3. tert-butyl(R)-((1-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate

To a solution of tert-Butyl(R)-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate (360 mg, 1.35mmol) in THF was added 4,4-difluorocyclohexanone (290 mg, 2.16 mmol) andsodium triacetoxyborohydride (460 mg, 2.16 mmol) and the reactionstirred for 16 hours. Saturated NaHCO₃ (75 mL) was added to the reactionmixture followed by extraction with EtOAc (3×75 mL). The combinedorganic fractions were washed with water (40 mL) and brine (40 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The crude was purified by column chromatography (SiO₂) elutingwith a gradient of 0-10% methanol in dichloromethane to provide 520 mg(100% yield) of product that was used in the next step without furtherpurification. ESMS (M+1)=385.69.

Step 4:(R)-(1-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methanaminedihydrochloride

To a solution of tert-butyl(R)-((1-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate(515 mg, 1.340 mmol) in dichloromethane (8 mL) was added 4 M HCl inmethanol (4 ml, 16.00 mmol) and the mixture stirred for 3 hours. Thereaction was concentrated to dryness under vacuum to provide 550 mg(100% yield) of the product. ESMS (M+1)=285.34.

B-161.(S)-(1-(1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methanaminedihydrochloride

The compound was prepared in a similar manner as reported for B-160 toprovide the title product, 510 mg (90% yield). ESI-MS (M+1)=285.38.

B-162.(S)-(1-(1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methanaminehydrochloride Step 1: Benzyl(S)-3-(4-(((tert-butoxycarbonyl)amino)methyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

Sodium hydride (540 mg, 13.5 mmol) was added to a mixture of tert-butylN-(1H-pyrazol-4-ylmethyl)carbamate (1.78 g, 9.0 mmol) in DMF (12 mL) at10° C. The mixture was stirred for 30 minutes then warmed to roomtemperature. Benzyl (3R)-3-(p-tolylsulfonyloxy)pyrrolidine-1-carboxylate(4.4 g, 11.7 mmol) was added to the mixture and stirred overnight. Thereaction was diluted with ethyl acetate (300 ml) and washed with 0.5NHCl (75 ml), saturated sodium bicarbonate (75 ml), and brine (100 ml).The organic layer was dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude product was purified by columnchromatography (SiO₂) eluting with a gradient of 0-100% ethyl acetate indichloromethane to provide 1.99 g (55% yield) of title compound. ESMS(M+1)=399.42.

Step 2: tert-Butyl(S)-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate

To a slurry of 10% Pd/C (100 mg) in methanol (20 ml) was added benzyl(S)-3-(4-(((tert-butoxycarbonyl)-amino)methyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate(1.59 mg, 3.97 mmol) in methanol (20 ml). A hydrogen atmosphere viaballoon was added and the reaction was stirred overnight. The mixturewas filtered and concentrated to dryness under vacuum provided toprovide 0.99 g (94% yield) of crude product. ESMS (M+1)=267.38.

Step 3. tert-butyl(S)-((1-(1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate

To a mixture of tert-Butyl(S)-((1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate (370 mg,1.389 mmol), (4-fluorophenyl)boronic acid (310.9 mg, 2.2 mmol),anhydrous copper acetate (379 mg) and 4A molecular sieves (700 mg) indichloromethane (10 mL) was added pyridine (170 μL, 2.1 mmol). Theresulting mixture was stirred at room temperature under a drierite tubefor 70 hours. The mixture was filtered over a pad of silica gel elutingwith 10% methanol in dichloromethane and concentrated to dryness undervacuum. The crude product was purified by column chromatography (SiO₂)eluting with a gradient of 0-100% ethyl acetate in dichloromethane toprovide the title compound, 140 mg (28% yield). ESMS (M+1)=361.3.

Step 4:(S)-(1-(1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

To a solution of tert-butyl(S)-((1-(1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate(236 mg, 0.65 mmol) in dichloromethane (3 mL) was added 2 M hydrogenchloride (2.5 ml of 2 M, 5.000 mmol) in diethyl ether. The resultingmixture was stirred for 3 hours. The reaction was concentrated todryness to provide 133 mg (68% yield) of title product. ESMS(M+1)=261.4.

B-163.(R)-(1-(1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methanaminehydrochloride

The compound was prepared in a similar manner as reported for B-162 toprovide the title product, 510 mg (90% yield). ESI-MS (M+1)=261.38.

B-164.(1-((6-Fluoro-5-methoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ7.92 (d, J=2.4 Hz, 1H), 7.77-7.60 (m, 2H), 7.62-7.49 (m, 1H), 5.42 (d,J=2.4 Hz, 2H), 4.09 (s, 2H), 3.94 (t, J=2.4 Hz, 3H). ESMS (M+1)=237.5.

B-165.(3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamineStep 1: Ethyl3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate

Di-(tert-Butyl)-azodicarboxylate (1.98 g, 8.6 mmol) was added dropwiseto a cooled (0° C.) solution of ethyl 3-bromo-1H-pyrazole-4-carboxylate(1.57 g, 7.17 mmol), [6-(trifluoromethyl)-3-pyridyl]methanol (1.3 g,7.34 mmol), and triphenylphosphine (2.26 g, 8.6 mmol) in dichloromethane(40 mL) and stirred for 30 min. The reaction was allowed to warm to roomand stirred overnight. The solution was then poured onto ice water (20ml) and extracted with dichloromethane. The reaction was evaporated invacuo to give a viscous oil. The residue was purified by columnchromatography (SiO₂, 4 g) eluting with a gradient of hexanes to 50%ethyl acetate. The desired fractions were combined and evaporated toprovide the title product as clear oil (1.3 g, 48% yield). 1H NMR (300MHz, CDCl₃) δ 8.78-8.56 (m, 1H), 7.92 (s, 1H), 7.85-7.73 (m, 1H), 7.70(dd, J=8.1, 0.8 Hz, 1H), 5.37 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.34 (t,J=7.1 Hz, 3H). ESI-MS m/z calc. 376.9987, found 378.08 (M+1)⁺;

Step 2:(3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanol

A 1M solution of DIBAL (9.9 ml, 9.9 mmol) in toluene was added to acooled (−78° C.) solution of ethyl3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazole-4-carboxylate(1.25 g, 3.306 mmol) in THE (10 mL). The reaction was warmed to 0° C.and stirred for 2 hours. The reaction was quenched by the addition ofEtOAc (30 mL). After stirring for 15 mins, Rochelle salt solution (30mL) was added. Ethyl acetate (25 ml) was added and the organic layer wasseparated. The aqueous layer was extracted with ethyl acetate (2×20 mL).The combined organic layers was dried over magnesium sulfate, filtered,and evaporated to give a light yellow sticky oil (1.1 g, 100% yield).This was used in the next step without further purification.

Step 3:5-((4-(Azidomethyl)-3-bromo-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)pyridine

DBU (600 uL, 3.95 mmol) was added dropwise to a cooled solution (0° C.)of(3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanol(1.1 g, 3.27 mmol) and diphenylphosphoryl azide (900 uL, 4.1 mmol) inanhydrous THE (20 ml). After 10 mins, the reaction turned cloudy. Thereaction was warmed to room temperature and stirred overnight. Thereaction turned to a clear tan color solution. The reaction was dilutedwith ethyl acetate (30 ml) and washed with aqueous ammonium chloride (10ml) and brine (10 ml). The organic layer was dried over MgSO₄, filteredand evaporated in vacuo to afford a tan oil that was purified by columnchromatography (SiO₂) eluting with a gradient of hexanes to 30% ethylacetate. The desired fractions were combined and evaporated to affordthe title product as a white solid (1.18 g, 66% yield). 1H NMR (300 MHz,CDCl₃) δ 8.70-8.58 (m, 1H), 7.71 (qd, J=8.2, 1.5 Hz, 2H), 7.44 (s, 1H),5.36 (s, 2H), 4.21 (s, 2H).

Step 4:(3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamine

Triphenylphosphine (860 mg, 3.24 mmol) was added to a solution of5-((4-(Azidomethyl)-3-bromo-1H-pyrazol-1-yl)methyl)-2-(trifluoromethyl)pyridine(782 mg, 2.16 mmol) in THE (18 mL) and water (2 mL) and stirredovernight at room temperature. The reaction was concentrated to removemost of the solvent. Aqueous 2 N HCl (20 mL) and dichloromethane (20 mL)was added to the residue. The organic layer was separated and theaqueous layer was washed with dichloromethane (10 mL×2). The aqueouslayer was concentrated to give a white solid that was dried under vacuumat 60° C. for 16 hours to afford the title product (745 mg, 93% yield).1H NMR (400 MHz, Methanol-d4) δ 8.65-8.58 (m, 1H), 7.98 (d, J=1.0 Hz,1H), 7.92 (dd, J=8.2, 2.1 Hz, 1H), 7.77 (dd, J=8.2, 0.8 Hz, 1H), 5.47(s, 2H), 3.95 (s, 2H). ESI-MS m/z calc. 334.0041, found 335.03 (M+1)⁺.

B-166.(1-((6-(Difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

The compound was prepared by method B. 1H NMR (300 MHz, Methanol-d4) δ8.22-8.10 (m, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.81-7.70 (m, 1H), 7.62 (d,J=0.8 Hz, 1H), 7.76-7.27 (t, J=73.0 Hz, 1H), 6.95 (dd, J=8.5, 0.7 Hz,1H), 5.36 (s, 2H), 4.03 (s, 2H). ESMS (M+1)=255.21.

B-167.(1-((2-Chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

The compound was prepared by Method B ESMS (M+1)=290.16.

B-168.(1-((6-Chloro-5-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.18-8.04 (m, 1H), 7.95-7.82 (m, 1H), 7.63 (s, 1H), 7.59 (dd, J=8.9, 2.0Hz, 1H), 5.42 (s, 2H), 4.02 (s, 2H). ESMS (M+1)=241.07.

B-169.(1-((5-Fluoro-6-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.18 (s, 1H), 7.88 (s, 1H), 7.62 (d, J=0.8 Hz, 1H), 7.42 (dd, J=10.0,1.7 Hz, 1H), 5.39 (s, 2H), 4.02 (s, 2H), 2.46 (d, J=2.9 Hz, 3H). ESMS(M+1)=221.11.

B-170. 5-((4-(Aminomethyl)-1H-pyrazol-1-yl)methyl)picolinonitrile

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.64-8.54 (m, 1H), 7.97 (s, 1H), 7.87-7.79 (m, 2H), 7.68 (d, J=3.8 Hz,1H), 5.51 (d, J=11.5 Hz, 2H), 4.09 (s, 3H). ESMS (M+1)=214.13.

B-171.(1-((6-Cyclopropylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.50 (d, J=2.0 Hz, 1H), 8.21-8.09 (m, 1H), 7.96 (s, 1H), 7.66 (s, 1H),7.55 (d, J=8.5 Hz, 1H), 5.51 (s, 2H), 4.05 (s, 2H), 2.32 (tt, J=8.7, 4.9Hz, 1H), 1.53-1.30 (m, 3H), 1.28-1.06 (m, 2H). ESMS (M+1)=229.22.

B-172.(1-(2-(6-(Trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)methanamine

The compound was prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.52(s, 1H), 7.93 (s, 6H), 7.82 (d, J=1.1 Hz, 1H), 7.71 (s, 1H), 7.52 (s,1H), 4.44 (t, J=6.9 Hz, 2H), 3.85 (dd, J=7.1, 4.4 Hz, 3H), 3.23 (t,J=6.9 Hz, 2H). ESMS (M+1)=271.25.

B-173.cis-3-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)cyclobutan-1-aminehydrochloride Step 1: tert-butyl(cis-3-(2-((((Z)-1-amino-2,2,2-trifluoroethylidene)amino)oxy)-2-oxoethyl)cyclobutyl)carbamate

Carbonyl diimidazole (450 mg, 2.8 mmol) was added to a solution ofcis-2-[3-(tert-Butoxycarbonylamino)cyclobutyl]acetic acid 527 mg, 2.3mmol) in dichloromethane (8 ml) and stirred at room temperature. After 5minutes, 2,2,2-trifluoro-N′-hydroxy-acetamidine (300 mg, 2.3 mmol) wasadded and the reaction was stirred at RT for 2 hours. The reaction wasevaporated in vacuo to dryness and carried on to Step 2.

Step 2: tert-butyl(cis-3-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)cyclobutyl)carbamate

The crude product from Step 1 was dissolved in 10 ml of toluene andrefluxed for 12 hours. The reaction mixture was evaporated in vacuo andthe crude purified by column chromatography (SiO₂) eluting with agradient of heptanes to 100% ethyl acetate. The relevant fractions werecombined and evaporated in vacuo to afford the title product (249 mg,34% yield). 1H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 4.66 (s, 1H), 4.03(s, 1H), 3.10 (d, J=7.3 Hz, 2H), 2.72-2.56 (m, 2H), 2.57-2.43 (m, 1H),1.79-1.66 (m, 2H), 1.46 (s, 9H). ESI-MS m/z calc. 321.13004, found 325.3(M+1)⁺

Step 3:cis-3-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)cyclobutan-1-aminehydrochloride

tert-Butyl(cis-3-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)cyclobutyl)carbamate(239 mg, 0.74 mmol) was dissolved in methanol (8 ml) and a 4M solutionof HCl in dioxane was added and the mixture heated at 50° C. for 20mins. The reaction was evaporated in vacuo to afford a solid. This waswashed with diethyl ether and hexanes, filtered and dried to afford thetitle product as a white solid (171 mg, 89% yield). 1H NMR (400 MHz,Methanol-d4) δ 3.71 (p, J=8.3 Hz, 1H), 3.23 (d, J=7.1 Hz, 2H), 2.76-2.55(m, 3H), 2.00 (qd, J=9.5, 8.9, 2.5 Hz, 2H). ESI-MS m/z calc. 221.07759,found 222.1 (M+1)⁺

B-174. (1-((5-fluoropyridin-2-yl)methyl)-1H-pyrazol-4-yl)methanamine

The compound was prepared by Method B. ESMS (M+1)=207.28.

B-175. (1-(4-(Trifluoromethoxy)benzyl)-1H-pyrazol-4-yl)methanaminehydrochloride

The compound was prepared by Method B. ESMS (M+1)=272.17.

B-176. (1-(6-(Trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methanamineStep A. tert-butyl((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate

A 2M solution of sodium t-butoxide (3.8 ml, 7.6 mmol) in THF was addedto a suspension of (tert-Butyl ((1H-pyrazol-4-yl)methyl)carbamate (500mg, 2.54 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (573 mg, 2.54mmol) in tert-butanol (12.5 ml) in a sealed tube. The mixture wassonicated for 10 mins. until mixed well. The mixture was degassed withnitrogen followed by the addition of t-BuXPhos palladacycle Gen 2 (0.06equiv.). The reaction was sealed and heated at 60 C for 1 hour. Thecrude product was purified by column chromatography (SiO₂) eluting agradient of dichloromethane to 20% methanol in dichloromethane. Thedesired fraction were collected, treated with Biotage MP-TMT resin,filtered, and evaporated to provide the title product that was usedwithout for further purification.

1H NMR (300 MHz, DMSO-d6) δ 9.26 (d, J=2.5 Hz, 1H), 8.57 (s, 1H), 8.45(dd, J=8.4, 2.6 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.78 (s, 1H), 7.27 (s,1H), 4.08 (d, J=5.9 Hz, 2H), 1.40 (s, 9H). ESMS (M+1)=343.32.

Step B. (1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methanaminetrifluoroacetate

tert-Butyl((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methyl)carbamate(105 mg, 0.03 mmol) was dissolved in dichloromethane and TFA (25 uL,0.03 mmol) was added and the reaction stirred at room temperature for 3hours. The reaction was evaporated in vacuo to afford 109 mg of thedesired product. 1H NMR (300 MHz, DMSO-d6) δ 9.28 (d, J=2.6 Hz, 1H),8.77 (s, 1H), 8.48 (dd, J=8.7, 2.6 Hz, 1H), 8.28-8.03 (m, 4H), 7.99 (s,1H), 4.03 (q, J=5.7 Hz, 2H). ESMS (M+1)=243.23.

B-177.(1-((6-(tert-Butyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamine

The compound was prepared by Method B. 1H NMR (300 MHz, CDCl₃) δ8.50-8.42 (m, 1H), 7.54-7.44 (m, 2H), 7.41-7.30 (m, 2H), 5.25 (s, 2H),4.70 (s, 1H), 4.16 (d, J=5.8 Hz, 2H), 1.45 (s, 9H), 1.36 (s, 9H). ESMS(M+1)=345.34.

B-178.2-(5-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-2-methylpropanenitrile

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.49 (d, J=2.3 Hz, 1H), 7.90 (s, 1H), 7.75 (dd, J=8.2, 2.4 Hz, 1H),7.68-7.52 (m, 2H), 5.42 (s, 2H), 4.04 (s, 2H), 1.72 (s, 6H). ESMS(M+1)=256.21.

B-179.(1-((6-(prop-1-en-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamineStep A. tert-Butyl((1-((6-(prop-1-en-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate

tert-Butyl((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (970mg, 3 mmol) and isopropenylboronic acid (515 mg, 6 mmol) was taken into15 ml of anhydrous dioxane and degassed by with nitrogen. Pd(dppf)Cl2was added to the mixture and the reaction heated at 80 C for 7 days. Thesolvent was evaporated in vacuo. The resulting residue was taken intoethyl acetate (20 ml) and washed with water (2×10 ml) and brine. Theorganic layer was collected and dried over anhydrous sodium sulfate,filtered, and evaporated to provide the crude product that was purifiedby column chromatography (SiO₂) eluting with a gradient of hexanes to50% ethyl acetate. The desired fractions were combined an devaporated toprovide the desired product as a light brown solid (530 mg, 49.9%yield). 1H NMR (300 MHz, CDCl₃) δ 8.54-8.38 (m, 1H), 7.58-7.42 (m, 3H),7.37 (s, 1H), 5.85 (dd, J=1.6, 0.9 Hz, 1H), 5.40-5.19 (m, 3H), 4.76 (s,1H), 4.14 (dd, J=8.3, 6.3 Hz, 3H), 2.20 (dd, J=1.5, 0.8 Hz, 3H), 1.44(s, 9H). ESMS (M+1)=329.17.

Step B.(1-((6-(prop-1-en-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoro acetic acetate

The compound was prepared by deprotection of the Boc protecting bytreating with TFA to afford the desired product. 1H NMR (300 MHz,Methanol-d4) δ 8.52 (s, 1H), 8.01 (dd, J=17.4, 8.0 Hz, 2H), 7.93 (d,J=3.4 Hz, 1H), 7.66 (d, J=5.0 Hz, 1H), 5.90 (d, J=2.3 Hz, 1H), 5.57 (d,J=8.0 Hz, 2H), 5.50 (s, 2H), 2.23 (dq, J=1.5, 0.7 Hz, 3H). ESMS(M+1)=229.18.

B-180.(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methanamineStep A.1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

1H-imidazole-4-carbonitrile (300 mg, 3.22 mmol) and5-(chloromethyl)-2-(trifluoromethyl)pyridine (662 mg, 3.385 mmol) weretaken into anhydrous DMF (5 ml) and cooled to 0° C. Sodium hydride (150mg, 3.7 mmol) was added to the solution portionwise and stirred at roomtemperature for 2 hours. The reaction was quenched with saturatedammonium chloride (10 ml) followed by evaporation of the solvent invacuo. The residue was suspended in dichloromethane (20 ml) and water(20 ml). The aqueous layer was extracted further with dichloromethane(20 ml). The organic layers were combined, washed with water and brine,dried over anhydrous sodium sulfate, filtered, and evaporated in vacuoto provide the crude product which was purified by column chromatography(SiO₂) eluting with a gradient of heptanes to 100% ethyl acetate toprovide the title product as a white solid (79 mg, 9.7% yield). 1H NMR(300 MHz, CDCl₃) S H NMR (300 MHz, (m, 1H), 8.79-8.57 (m, 1H), 8.50-8.23(m, 1H), 8.02-7.83 (m, 2H), 7.84-7.72 (m, 1H), 5.56 (s, 2H).

Step B. tert-butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methyl)carbamate

1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile(80 mg, 0.32 mmol), dichlorocobalt hexahydrate (15 mg, 0.063 mmol) anddi-tert-butyl dicarbonate (83.5 mg, 0.3826 mmol) were taken intomethanol and cooled to 0° C. followed by the addition of sodiumborohydride (36.5 mg, 0.96 mmol) portionwise. The reaction was stirredfor 2 hours. After evaporation of the reaction, dichloromethane andwater was added and the organic layer was collected and filtered toremove the solid suspension. The organic layer was washed with brine,dried over anhydrous magnesium sulfate, and evaporated in vacuo toprovide the crude product which was purified by column chromatography(SiO₂, 4 g) eluting with a gradient of dichloromethane to 10% methanolto afford the title product as a white solid (67 mg, 57% yield). 1H NMR(300 MHz, CDCl₃) δ 8.48-8.29 (m, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.49-7.33(m, 2H), 7.05-6.83 (m, 1H), 5.28 (s, 2H), 5.17 (t, J=6.9 Hz, 1H), 4.18(d, J=6.1 Hz, 2H), 1.25 (s, 9H); 19 F NMR (282 MHz, CDCl₃) δ −67.91.

Step C.(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methanamine

tert-Butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methyl)carbamate(68 mg, 0.1822 mmol) was taken into dichloromethane and TFA (207.8 mg,140.4 μL, 1.822 mmol) and stirred at room temperature for 1 hour. Thereaction was evaporated in vacuo to provide a residue that wastriturated with diethyl ether to afford the product as a white solid (67mg (100% yield) that was used without further purification.

B-181. (1-((2-chlorothiazol-5-yl)methyl)-1H-pyrazol-4-yl)methanamine

The compound was prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 7.66(m, 2H), 7.36 (d, J=0.8 Hz, 1H), 7.16 (t, J=5.7 Hz, 1H), 5.52 (s, 2H),3.93 (d, J=6.0 Hz, 2H), 1.37 (s, 9H). ESMS (M+1)=329.08.

B-182.(1-((6-(difluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamine

The compound was prepared by Method B. ESMS (M+1)=239.13.

B-183.(1-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-1H-pyrazol-4-yl)methanaminetrifluoro acetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, DMSO-d6) δ 8.62(d, J=2.1 Hz, 1H), 7.99 (s, 3H), 7.93 (dd, J=8.2, 2.1 Hz, 1H), 7.87-7.78(m, 2H), 7.53 (s, 1H), 4.14 (t, J=6.9 Hz, 2H), 3.90 (q, J=5.7 Hz, 2H),2.67 (t, J=7.6 Hz, 2H), 2.20-2.01 (m, 2H). ESMS (M+1)=285.21

B-184.(1-((6-(trifluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoro acetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.27 (d, J=2.5 Hz, 1H), 7.95-7.91 (m, 1H), 7.91-7.82 (m, 1H), 7.67 (s,1H), 7.17 (d, J=8.5 Hz, 1H), 5.46 (s, 2H), 4.07 (s, 2H). ESMS(M+1)=273.23.

B-185.(1-((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride

The compound was prepared by Method B. 1H NMR (300 MHz, Methanol-d4) δ8.65-8.54 (m, 1H), 8.04-7.93 (m, 2H), 7.80 (dd, J=8.2, 0.8 Hz, 1H), 7.67(s, 1H), 5.52 (s, 2H), 4.05 (s, 2H), 1.99 (td, J=18.7, 0.6 Hz, 3H). ESMS(M+1)=253.14.

B-186. (1-((2-isopropyloxazol-5-yl)methyl)-1H-pyrazol-4-yl)methanaminefluoroacetic acid

The compound was prepared by Method B. 1H NMR (300 MHz, CD₃OD) δ7.94-7.71 (m, 2H), 7.59 (s, 1H), 5.22 (s, 2H), 4.02 (s, 2H), 3.17-2.94(m, 1H), 1.41-1.15 (m, 6H).

B-187.(1-(3,5-difluoro-4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)methanamine Step1: 1-(3,5-difluoro-4-methoxybenzyl)-1H-1,2,4-triazole-3-carbonitrile

1H-1,2,4-triazole-3-carbonitrile (2 g, 21.26 mmol),5-(bromomethyl)-1,3-difluoro-2-methoxy-benzene (5.55 g, 23.4 mmol), andpotassium carbonate were taken into acetonitrile (20 ml) and stirred atroom temperature for 3 days. The reaction was diluted with 20 ml ofwater and extracted with ethyl acetate (3×20 ml). The combined extractswas washed with brine, dried over anhydrous sodium sulfate, filtered,and evaporated in vacuo to afford the crude product. as a white solidthat was purified by column chromatography elutine with a gradient ofheptanes to 100% ethyl acetate to provide the title product as a whitesolid (2.33 g, 43% yield). 1H NMR (300 MHz, Methanol-d4) δ 9.01 (s, 1H),7.21 (m, 2H), 5.5 (s, 2H), 3.92 (s, 3H).

Step 2:(1-(3,5-difluoro-4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)methanamine

1-(3,5-difluoro-4-methoxybenzyl)-1H-1,2,4-triazole-3-carbonitrile (1 g,4 mmol) was added to a slurry of raney nickel in methanol and ammoniaand placed on the Paar shaker under 50 psi of hydrogen. The reactionmixture was filtered through Celite and the filtrate evaporated invacuo. The crude product was purified by column chromatography (SiO₂)eluting with a gradient of dichloromethane to 70% ethyl acetate toafford the title product as a white solid (796 mg, 78% yield); ESMS(M+1)=255.11.

B-188. (1-(4-(trifluoromethoxy)benzyl)-1H-1,2,4-triazol-3-yl)methanamine

The compound was prepared in 2 steps by the procedure reported forB-187. ESMS (M+1)=273.12.

B-189. (1-(3,4,5-trifluorobenzyl)-1H-1,2,4-triazol-3-yl)methanamine

The compound was prepared in 2 steps by the procedure reported forB-187; ESMS (M+1)=243.09.

B-190.1-[3-[[4-(aminomethyl)pyrazol-1-yl]methyl]-6-(trifluoromethyl)-2-pyridyl]ethanonehydrochloride Step 1: tert-Butyl((1-((2-acetyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate

Sodium periodate (4.32 g, 20.20 mmol) was added to a solution oftert-butyl((1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate,B-81 (2 g, 5.045 mmol) in THF (10.00 mL), acetone (10.00 mL), and water(10.00 mL) and cooled in an ice bath. Trichlororuthenium monohydrate (46mg, 0.204 mmol) was added to the mixture and stirred for 2 hours. Thereaction was filtered through Celite and the filtrate evaporated invacuo. The resulting residue was dissolved in dichloromethane and washedwith brine. The organic layer was dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo. The crude oil was purified by columnchromatography (SiO₂) eluting with a gradient of heptane to 60% ethylacetate. Evaporation of the desired fractions afforded the product (1.6g) that was used immediately in the next step.

Step 2:1-(3-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)ethan-1-onehydrochloride

tert-Butyl((1-((2-acetyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(1.6 g) was taken into dichloromethane (10 ml) and 2.1 ml of TFA andstirred for 2 hours. The reaction was evaporated in vacuo and theresulting oil was dissolved in dichloromethane and washed with 10%sodium carbonate. The organic layer was dried over anhydrous sodiumsulfate, filtered and evaporated. The resulting oil was dissolved indiethyl ether and 5 ml of 1N HCl in diethyl ether was added resulting ina white solid that was collected and dried to afford the title product(1.03 g, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.27 (s, 3H), 8.09 (d,J=8.2 Hz, 1H), 7.97 (s, 1H), 7.67 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 5.76(d, J=2.7 Hz, 2H), 3.91 (q, J=5.6 Hz, 2H), 2.68 (s, 3H). ESI-MS m/zcalc. 298.10416, found 299.13 (M+1)+.

B-191.(trans-4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclohexyl)methanamineStep 1: tert-Butyl((trans-4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclohexyl)methyl)carbamate

Diisopropyl azodicarboxylate (500 uL, 2.59 mmol) was added dropwise to asolution of tert-butyl((trans-4-(hydroxymethyl)cyclohexyl)methyl)carbamate (525 mg, 2.16mmol), 6-(trifluoromethyl)pyridin-3-ol (410 mg, 2.514 mmol), andtriphenylphosphine (854 mg, 3.26 mmol) in THE (15 ml) and the reactionstirred overnight. Water (25 ml) was added to the reaction mixturefollowed by extraction with ethyl acetate (3×25 ml). The combinedorganic extracts were washed with brine, dried over anhydrous sodiumsulfate, filtered, and evaporated in vacuo to afford the crude product.This was purified by column chromatography (SiO₂) eluting with agradient of 0-100% dichloromethane-ethyl acetate. The desired fractionswere combined and evaporated to afford the title product (670 mg, 13%yield). 1H NMR (300 MHz, CD₃CN) δ 8.38 (d, J=2.8 Hz, 1H), 7.72 (d, J=8.7Hz, 1H), 7.44 (dd, J=8.6, 2.6 Hz, 1H), 5.30 (s, 1H), 3.95 (d, J=6.4 Hz,2H), 2.91 (t, J=6.4 Hz, 2H), 2.12 (d, J=10.0 Hz, 2H), 1.91-1.69 (m, 4H),1.40 (d, J=16.5 Hz, 10H), 1.28-0.85 (m, 5H).

Step 2:(trans-4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclohexyl)methanaminedihydrochloride

tert-Butyl((trans-4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclohexyl)methyl)carbamate(670 mg) was taken into 10 ml of dichloromethane. A solution of 4M HCl(2 ml, 8 mmol) in dioxane was added to the solution and stirred for 1hour. The reaction was evaporated in vacuo to afford a solid that waswashed with diethyl ether and hexanes, filtered and evaporated to affordthe title product (411 mg). 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=2.8Hz, 1H), 7.83 (d, J=8.7 Hz, 4H), 7.59 (dd, J=8.7, 2.6 Hz, 1H), 3.98 (d,J=6.3 Hz, 2H), 2.66 (s, 2H), 1.83 (dd, J=30.4, 16.5 Hz, 5H), 1.55 (s,1H), 1.21-0.80 (m, 4H). ESI-MS m/z calc. 288.14496, found 289.57 (M+1)⁺.

B-192. (1-(3,4,5-Trifluorobenzyl)-1H-1,2,3-triazol-4-yl)methanamine

5-(bromomethyl)-1,2,3-trifluoro-benzene (1 g, 4.44 mmol) was addeddropwise to a solution of sodium azide (315 mg, 4.85 mmol) in DMSO (30ml) and stirred at room temperature for 15 mins. Propargylamine (245 mg,4.44 mmol) was added to the solution followed by the addition oftriethylamine (100 uL, 0.66 mmol) and CuBr (637 mg, 4.44 mmol). Thereaction was stirred at room temperature for 30 mins. The reaction waspoured into ice water (200 ml) and the resulting precipitate wasfiltered and washed with dilute ammonium hydroxide and water. The crudesolid was purified by preparative reverse phase chromatography (C18column) eluting with 0 to 100% acetonitrile/water (TFA modifier). Thedesired fractions were combined and evaporated in vacuo to provide theproduct as a yellow oil (930 mg, 86% yield). ESMS (M+1)=243.15

B-193.(1-(3,5-Difluoro-4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanamine

The compound was prepared by the same procedure as B-192 to provide thedesired product. ESMS (M+1)=255.17.

B-194.(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methanamineStep 1:1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile

1H-imidazole-4-carbonitrile (300 mg, 3.22 mmol) andchloromethyl)-2-(trifluoromethyl)pyridine (662 mg, 3.385 mmol) weretaken into anhydrous DMF (5 ml) and cooled to 0° C. Sodium hydride (150mg, 3.72 mmol) was added to the mixture portionwise then warmed to roomtemperature. After stirring for 2 hours, the reaction was quenched withsaturated ammonium chloride (10 ml). The mixture was diluted withdichloromethane (25 ml) and water (20 ml) and the layers separated. Theaqueous was extracted with dichloromethane (2×10 ml). The combinedorganic extracts was washed with water (10 ml) and brine (2×10 ml),dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo.The crude product was purified by column chromatography (SiO₂) elutingwith to provide a white solid (79 mg, 9.7% yield). 1H NMR (300 MHz,CDCl₃) δ H NMR (300 MHz, (m, 1H), 8.79-8.57 (m, 1H), 8.50-8.23 (m, 1H),8.02-7.83 (m, 2H), 7.84-7.72 (m, 1H), 5.56 (s, 2H).

Step 2: tert-Butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methyl)carbamate

1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazole-4-carbonitrile(79 mg, 0.32 mmol), dichlorocobalt hexahydrate (15 mg, 0.063 mmol) andBoc₂O (83 mg, 0.383) were taken into methanol and cooled to 0° C. Sodiumborohydride (36.5 mg, 0.96 mmol) was added to the solution portionwiseand stirred for 2 hours. The reaction was evaporated in vacuo. The blackresidue was suspended in dichloromethane and water. The organic layerwas collected and filtered to remove solid suspension. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate filtered,and evaporated in vacuo. The resulting residue was purified by columnchromatography (SiO₂, 4 g) eluting with a gradient of 0-10% methanol indichloromethane, The desired fractions were combined and evaporated invacuo to afford the title product as a white solid (67 mg, 57% yield).1H NMR (300 MHz, CDCl₃) δ 8.48-8.29 (m, 1H), 7.57 (d, J=8.1 Hz, 1H),7.49-7.33 (m, 2H), 7.05-6.83 (m, 1H), 5.28 (s, 2H), 5.17 (t, J=6.9 Hz,1H), 4.18 (d, J=6.1 Hz, 2H), 1.25 (s, 9H). ESMS (M+1)=357.19.

Step 3:(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methanamine

tert-Butyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methyl)carbamate(68 mg, 0.182 mmol) was dissolved in dichloromethane (2 ml) and TFA (140uL, 1.82 mmol) and stirred at room temperature for 1 hour. The reactionwas evaporated in vacuo. The resulting residue was triturated withdiethyl ether to afford a white solid (68 mg, quantitative yield). Thecompound was used without further characterization.

B-195.cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutan-1-amineStep 1: tert-butyl(cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-cyclobutyl)carbamate

Diethyl azodicarboxylate (13 mL of 40% w/w, 28 mmol) was added dropwiseto a solution of tert-butyl (cis-3-(hydroxymethyl)-cyclobutyl)carbamate(4.699 g, 23.35 mmol), 6-(trifluoromethyl)pyridin-3-ol (4.2 g, 25.7mmol) and triphenylphosphine (7.349 g, 6.492 mL, 28.02 mmol) in THE (80mL) at room temperature and stirred for 1 hour. The solvent wasevaporated. The residue was dissolved in dichloromethane (100 ml) andwashed with 2N sodium hydroxide (2×). The solvent was evaporated invacuo to give an oil that was purified by column chromatography (SiO₂)eluting with a gradient hexanes to 100% ethyl acetate. The desiredfractions were evaporated to afford the title product (3.11 g, 38%yield). 1H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=2.8 Hz, 1H), 7.63 (d, J=8.7Hz, 1H), 7.29-7.20 (m, 1H), 4.73 (s, 1H), 4.17-4.08 (m, 1H), 4.02 (d,J=5.4 Hz, 2H), 2.68-2.37 (m, 3H), 1.91-1.75 (m, 2H), 1.47 (s, 9H).ESI-MS m/z calc. 346.15042, found 347.27 (M+1)⁺;

Step 2:cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutan-1-amine

tert-Butyl(cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)-cyclobutyl)carbamate(3.11 g, 9 mmol) was taken into a 4M solution of hydrogen chloride (25mL of 4 M, 100.0 mmol) in dioxane. After stirring for 2 hours, diethylether was added to the mixture and the white solid was collected anddried to afford a white solid: 2.42 g 1H NMR (400 MHz, DMSO-d6) δ 8.46(d, J=2.8 Hz, 1H), 8.16 (s, 3H), 7.85 (d, J=8.7 Hz, 1H), 7.61 (dd,J=8.7, 2.9 Hz, 1H), 4.14 (d, J=6.2 Hz, 2H), 3.63 (s, 1H), 2.57 (dt,J=7.9, 1.7 Hz, OH), 2.36 (tdd, J=9.4, 6.1, 2.2 Hz, 2H), 2.04 (d, J=10.2Hz, 2H). ESI-MS m/z calc. 246.09799, found 247.13 (M+1)⁺.

B-196.trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutan-1-amine Step1: tert-butyl(trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)-carbamate

Diethyl azodicarboxylate (3.375 g, 3.530 mL of 40% w/w, 7.752 mmol) wasadded to a solution of tert-butyl(cis-3-hydroxycyclobutyl)carbamatecarbamate (1.33 g, 7.11 mmol),2-(trifluoromethyl)pyrimidin-5-ol (1.06 g, 6.46 mmol) andtriphenylphosphine (2.033 g, 1.796 mL, 7.752 mmol) in THF (20 mL) wasadded a dropwise at room temperature. The reaction was heated to 50° C.for 1 hour. The reaction was evaporated in vacuo and the residuepurified by column chromatography (SiO2) eluting with a gradient ofheptane to 100% ethyl acetate. The desired fractions were combined andevaporated in vacuo to afford 1.79 g of the title product. 1H NMR (400MHz, CDCl₃) δ 8.40 (s, 2H), 5.02-4.86 (m, 1H), 4.80 (s, 1H), 4.35 (s,1H), 2.63 (ddd, J=11.7, 8.2, 3.4 Hz, 2H), 2.55 (d, J=5.7 Hz, 2H), 1.47(s, 9H).

Step 2:trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutan-1-amine

To tert-butyl(trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)-carbamate(1.77 g, 5.289 mmol) was added a solution of hydrogen chloride (27.58 mLof 4 M, 110.3 mmol) in dioxane and the mixture stirred at roomtemperature for 16 hours. A precipitate had formed. Diethyl ether wasadded to the mixture and stirred. The white solid was collected, washedwith diethyl ether, and dried under vacuum at 50° C. to afford the titleproduct as a white solid 1.28 g. 1H NMR (300 MHz, CD₃OD) δ 8.54 (s, 2H),5.16 (d, J=25.9 Hz, 1H), 4.05 (s, 1H), 2.74 (s, 4H).

B-9a. trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-aminehydrochloride B-197b.trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-aminehydrochloride Step 1: tert-butyl(trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate andtert-butyl(trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate

Diethyl azodicarboxylate (27 mL of 40% w/w, 59.29 mmol) was added to acooled (0° C.) mixture of tert-butyl (cis-3-hydroxycyclobutyl)carbamate(10.09 g, 53.89 mmol) and triphenylphosphine (15.78 g, 60.16 mmol) inTHE (150 mL) followed by the addition of 3-(trifluoromethyl)-4H-pyrazole(8.18 g, 60.11 mmol). The reaction was heated at 50° C. for 12 hours.The solvent was removed and the residue was purified by columnchromatography (SiO₂) eluting with a gradient of heptanes to ethylacetate isolating two regioisomers.

Peak 1 (minor product) as tert-butyl(trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate (4.09g, 24% yield) 1H NMR (400 MHz, CDCl₃) δ 7.57 (d, J=1.9 Hz, 1H), 6.62 (d,J=1.9 Hz, 1H), 5.06 (t, J=7.2 Hz, 1H), 4.81 (s, 1H), 4.39 (s, 1H), 3.02(ddd, J=13.7, 8.2, 5.7 Hz, 1H), 2.56 (d, J=21.7 Hz, 2H), 1.49 (d, J=2.1Hz, 9H). ESI-MS m/z 319.4.

Peak 2 (major product) as tert-butyl(trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate.(10.82 g, 64%) 1H NMR (400 MHz, CDCl₃) δ 7.54-7.42 (m, 1H), 6.54 (d,J=2.4 Hz, 1H), 5.00-4.87 (m, 1H), 4.81 (s, 1H), 4.37 (s, 1H), 3.00-2.84(m, 2H), 2.59 (s, 2H), 1.48 (s, 9H). ESI-MS m/z 319.4.

Step 2 B-197a.trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-aminehydrochloride

tert-Butyl(trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate (4.22g, 13.36 mmol) was dissolved in methanol (35 mL). A solution of 2 M HClin diethyl ether (31 mL, 62.00 mmol) was added and stirred at 50° C. for1 hour. The reaction was evaporated in vacuo and the resulting solid waswashed with diethyl ether and hexanes to provide the title product as awhite solid (3.1 g, 96% yield). 1H NMR (400 MHz, Methanol-d4) δ 7.67 (d,J=1.9 Hz, 1H), 6.77 (d, J=1.9 Hz, 1H), 5.34-5.27 (m, 1H), 4.19-4.11 (m,1H), 3.09-2.99 (m, 2H), 2.84-2.77 (m, 2H). ESI-MS m/z 206.08 (M+1)⁺.

B-197b. trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutan-1-aminehydrochloride

tert-Butyl(trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)carbamate(10.82 g, 35.44 mmol) was dissolved in methanol (100 mL). A solution of2M HCl in diethyl ether (80 mL, 160 mmol) was added to the solution andstirred at 50° C. for 1 hour. The reaction was evaporated in vacuo andthe resulting solid was washed with diethyl ether and hexanes to providethe title product as a white solid (8.37 g, 98% yield). 1H NMR (400 MHz,Methanol-d4) δ 7.82 (dd, J=2.4, 1.1 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H),5.17 (ddd, J=13.9, 9.0, 5.1 Hz, 1H), 4.17 (ttd, J=8.5, 5.8, 0.9 Hz, 1H),2.95 (dddt, J=14.0, 8.5, 5.5, 1.8 Hz, 2H), 2.87-2.69 (m, 2H). ESI-MS m/zcalc. 205.08269, found 219.85 (M+1)⁺.

B-198.cis-N1-methyl-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diamineStep 1: tert-butyl(cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)carbamate

A mixture of tert-butyl (cis-3-aminocyclobutyl)carbamate (2.0355 g,10.93 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (2.2 g, 12.05 mmol)and Diisopropylethylamine (2.86 mL, 16.42 mmol) were taken intoisopropanol (2 mL) was heated in a microwave tube for 1 hour at 150° C.The reaction was diluted with 100 ml of ethyl acetate and washed withbrine. The organic layer was dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo to afford a solid that was trituratedwith diethyl ether. The white solid was collected by vacuum filtrationto provide the title product as a white solid (3.32 g, 89% yield). 1HNMR (300 MHz, CDCl₃) δ 8.34 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 5.18 (s,1H), 4.71 (s, 1H), 3.92 (d, J=8.2 Hz, 1H), 3.51 (s, 1H), 2.95 (dtd,J=10.0, 7.3, 2.9 Hz, 2H), 1.90 (d, J=9.4 Hz, 2H), 1.47 (s, 9H). ESI-MSm/z 333.18 (M+1).

Step 2: tert-butyl(cis-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)carbamate

A mixture of tert-butyl(cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)carbamate (510mg, 1.496 mmol), cesium carbonate (975 mg, 2.992 mmol) and iodomethane(140 μL, 2.249 mmol) in DMF (8 mL) was stirred at room temperature for24 hours. The reaction mixture was evaporated in vacuo and the resultingresidue was treated with equal amounts of water and ethyl acetate (25ml). The organic layer was washed with brine, dried over anhydroussodium sulfate, filtered, and evaporate in vacuo to provide the product(518 mg, 99% yield). 1H NMR (400 MHz, CDCl₃) δ 8.39 (s, 1H), 8.03 (d,J=1.4 Hz, 1H), 4.70 (s, 1H), 4.46 (t, J=8.4 Hz, 1H), 3.90 (s, 1H), 3.13(s, 3H), 2.85-2.72 (m, 2H), 2.10 (t, J=10.8 Hz, 2H), 1.48 (s, 9H).ESI-MS m/z 347.23 (M+1)⁺

Step 3:cis-N1-methyl-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diamine

tert-Butyl(cis-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)carbamate(410 mg, 1.168 mmol) was taken into methanol (6 mL). A solution of HCl(6 mL of 4 M, 24.00 mmol) in dioxane was added and the reaction washeated at 50° C. The reaction was evaporated in vacuo and the resultingresidue triturated with heptanes then filtered to provide a white solid(430 mg, quantitative yield) as the title product. 1H NMR (400 MHz,Methanol-d4) δ 8.45-8.33 (m, 1H), 8.30-8.12 (m, 1H), 4.77 (tt, J=9.6,7.4 Hz, 1H), 3.61-3.54 (m, 1H), 3.19 (s, 3H), 2.83-2.70 (m, 2H), 2.43(dt, J=12.3, 8.9 Hz, 2H). ESI-MS 246.95 (M+1)⁺.

B-199.trans-N1-methyl-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diamine

The compound was prepared in a similar manner as B-198. 1H NMR (400 MHz,Methanol-d4) δ 8.39 (s, 1H), 8.24 (dt, J=4.3, 2.1 Hz, 1H), 5.40 (p,J=8.4 Hz, 1H), 3.99-3.83 (m, 1H), 3.22 (d, J=1.5 Hz, 3H), 2.93-2.78 (m,2H), 2.55 (ddt, J=11.8, 5.1, 2.9 Hz, 2H). ESI-MS m/z 247.13 (M+1)⁺.

B-200.(S)-(1-((1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)methanamineHydrochloride Step 1.(S)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)methanol

To a mixture of [(2S)-pyrrolidin-2-yl]methanol (600 mg, 5.9 mmol) and1,3,5-trifluorobenzene (1.02 g, 7.7 mmol) in DMSO (0.5 mL) was addedcesium fluoride (1.17 g, 7.7 mmol). The reaction was heated to 80° C.and stirred for 48 hours. Water (75 mL) was added to the reactionmixture followed by extraction with ethyl acetate (3×75 mL). Thecombined organic extracts were washed with water (2×40 mL) and brine(1×40 mL), dried over sodium sulfate, filtered, and evaporated in vacuoto provide 1.3 g (100% yield) of title compound that was used in steps.ESMS (M+1)=214.01.

Step 2. (S)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl4-methylbenzenesulfonate

To a solution of (S)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)methanol(1.1 g, 5.16 mmol) and triethylamine (1.1 g, 10.87 mmol) indichloromethane (15 mL) was added 4-methylbenzenesulfonyl chloride (1.1g, 5.77 mmol) and the reaction was stirred for 16 hours. Diethyl ether(100 ml) was added to the mixture and stirred. A precipitate formed thatwas filtered off and rinsed with diethyl ether (50 ml). The filtrate waswashed with saturated aqueous sodium bicarbonate (50 ml) and brine (50ml). The organic layer was dried over sodium sulfate, filtered, andevaporated in vacuo to provide 1.8 g (100% yield) of the title productthat was used without further purification in Step 3. ESMS (M+1)=368.32.

Step 3. tert-Butyl(S)-((1-((1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate

Sodium hydride (92 mg. 2.29 mmol) was added to a solution of tert-butylN-(1H-pyrazol-4-ylmethyl)carbamate (376 mg, 1.91 mmol) in DMF (4 mL) andstirred for 1 hour. (S)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl4-methylbenzenesulfonate (771 mg, 2.1 mmol) in 2 ml of DMF was addeddropwise and the reaction was stirred for 16 hours at room temperature.Water (75 mL) was added to the reaction mixture followed by extractionwith ethyl acetate (3×75 mL). The combined extracts were washed withwater (2×40 mL) and brine (40 mL), dried over sodium sulfate, filtered,and evaporated in vacuo. The crude product was purified by columnchromatography (SiO₂) eluting with a gradient of 0-100% ethyl acetate indichloromethane to provide the title product, wt. 555 mg (74% yield).ESMS (M+1)=393.43.

Step 4.(S)-(1-((1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)methanamineHydrochloride

To a mixture of tert-Butyl(S)-((1-((1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate(555 mg, 1.414 mmol) in dichloromethane (3 ml) was added a 1M solutionof HCl (10 ml, 10 mmol) in diethyl ether. The reaction was stirred for 2hours and additional 5 ml of 4M HCL (20 mmol) in dioxane was added. Thereaction stirred overnight and then evaporated in vacuo to provide thetitle compound, 104 mg (22% yield). ESMS (M+1)=293.44.

B-201: trans-3-((3,4-difluorobenzyl)oxy)cyclobutan-1-amine hydrochlorideStep 1. tert-butyl(trans-3-((3,4-difluorobenzyl)oxy)cyclobutyl)carbamate

Sodium hydride (329 mg, 8.23 mmol) was added to a cooled solution (0°C.) of tert-butyl (trans-3-hydroxycyclobutyl)carbamate 1.4 g, 7.48 mmol)and 3,4-difluorobenzyl bromide (1.01 g, 7.48 mmol) in DMF (10 ml) andstirred at room temperature. Water was added to the reaction and theresulting white precipitate was collected by vacuum filtration, washedwell with water, and dried under vacuum to provide the title product,2.01 g (89{circumflex over ( )}% yield). ESMS (M+1)=314.21

Step 2. trans-3-((3,4-difluorobenzyl)oxy)cyclobutan-1-aminehydrochloride

The compound was prepared by deprotection of tert-butyl(trans-3-((3,4-difluorobenzyl)oxy)cyclobutyl)carbamate (2.01 g, 6.415mmol) by dissolving in 20 mL of 4M HCl (80.00 mmol) in dioxane. Thereaction was stirred for 2 hours, then evaporated in vacuo to providethe title product as the hydrochloride salt, wt. 1.45 g (90.51% yield).ESMS (M+1)=214.16.

B-202 and B-203 were prepared in a similar manner as the proceduredescribed for B-201 B-202trans-3-((3,4,5-trifluorobenzyl)oxy)cyclobutan-1-amine hydrochloride

ESMS (M+1)=232.22.

B-203 cis-3-methyl-3-((3,4,5-trifluorobenzyl)oxy)cyclobutan-1-aminehydrochloride

ESMS (M+1)=246.18.

B-204.(1R,3R)—N1-methyl-N1-(4-(trifluoromethyl)phenyl)cyclopentane-1,3-diaminehydrochloride and B-205.(1S,3R)—N1-methyl-N1-(4-(trifluoromethyl)phenyl)cyclopentane-1,3-diaminehydrochloride Step 1: tert-butyl((1R,3R)-3-(methyl(4-(trifluoromethyl)phenyl)amino)-cyclopentyl)carbamateand tert-butyl((1R,3S)-3-(methyl(4-(trifluoromethyl)-phenyl)amino)cyclopentyl)-carbamate

Acetic acid (8 ml) was added to a mixture of tert-butyl(R)-(3-oxocyclopentyl)carbamate (773 mg, 3.880 mmol) andN-methyl-4-(trifluoromethyl)aniline (710 mg, 4.06 mmol) in methanol (8mL) and stirred at room temperature for 20 mins. Triethylsilane (1.25ml, 7.83 mmol) was added to the mixture followed by the addition ofIndium(III) chloride (260 mg, 1.17 mmol) and stirred at room temperaturefor 12 hours. The reaction was neutralized with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer wasseparated, dried over magnesium sulfate, filtered, and evaporated toafford the crude product. The crude product was purified by columnchromatography (SiO₂) eluting with a gradient of 0-100% ethyl acetate inheptanes to afford a mixture of the product as diastereomers (726 mg,52% yield). The diasteromers were separated by SFC (OJ-H column, 20×250mm; 10% methanol (5 mM ammonia)/90% CO₂, Isocratic, 80 ml/min) toprovide:

tert-butyl((1R,3R)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)-carbamate

(296 mg): SFC Rt 0.646 mins. 1H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=8.6Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 4.55 (s, 1H), 4.44 (dt, J=16.3, 8.3 Hz,1H), 4.11 (s, 1H), 2.85 (s, 3H), 2.26-2.16 (m, 1H), 2.13-2.00 (m, 2H),1.87-1.74 (m, 1H), 1.73-1.62 (m, 1H), 1.48 (s, 9H). ESI-MS m/z calc.358.1868, found 359.25 (M+1)⁺; [α]=43.3° (c=1.0, methanol).

tert-butyl((1R,3S)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)-carbamate

(312 mg): SFC Rt 0.79 mins. 1H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=8.6 Hz,2H), 6.79 (d, J=8.8 Hz, 2H), 4.58 (s, 1H), 4.28 (dq, J=15.9, 8.0 Hz,1H), 3.97 (s, 1H), 2.87 (s, 3H), 2.47-2.31 (m, 1H), 2.18-2.05 (m, 1H),1.96 (dt, J=14.5, 8.1 Hz, 1H), 1.85-1.72 (m, 1H), 1.56 (ddd, J=18.3,9.3, 6.2 Hz, 1H), 1.47 (s, 9H). ESI-MS m/z calc. 358.1868, found 359.25(M+1)⁺; [α]=−46° (c=1.0, methanol).

Step 2: B-204.(1R,3R)—N1-methyl-N1-(4-(trifluoromethyl)phenyl)cyclopentane-1,3-diaminehydrochloride

The compound was prepared by deprotection of tert-butyl((1R,3R)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)-carbamate(296 mg) in methanol (6 ml) and 4 M HCl in dioxane (6 ml). Evaporationof the reaction afforded the title product as a hydrochloride salt (290mg). 1H NMR (400 MHz, CD₃OD) δ 4.68 (s, 1H), 3.95 (s, 1H), 3.66 (s, 3H),2.36 (d, J=46.8 Hz, 2H), 2.11 (t, J=39.1 Hz, 3H), 1.81 (s, 1H); ESI-MSm/z calc. 258.13437, found 259.2 (M+1)⁺.

B-205.(1S,3R)—N1-methyl-N1-(4-(trifluoromethyl)phenyl)cyclopentane-1,3-diaminehydrochloride

The compound was prepared by the same procedure to provide product asthe HCl salt (320 mg). 1H NMR (400 MHz, CD₃OD) δ 8.15 (d, J=8.1 Hz, 2H),7.97 (d, J=8.3 Hz, 2H), 4.64-4.42 (m, 1H), 3.87-3.71 (m, 1H), 3.66-3.56(m, 1H), 3.38 (s, 3H), 2.52 (s, 1H), 2.16 (ddd, J=60.7, 30.2, 11.4 Hz,5H). ESI-MS m/z calc. 258.13437, found 259.2 (M+1)⁺;

B-206.(1R,3S)—N1-methyl-N1-(4-(trifluoromethyl)phenyl)cyclopentane-1,3-diaminehydrochloride

The compound prepared in the same manner as B-204 & B-205 to provide theproduct. 1H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=7.7 Hz, 2H), 7.98 (d,J=7.6 Hz, 2H), 4.53 (d, J=43.6 Hz, 1H), 3.86-3.72 (m, 1H), 3.38 (d,J=17.7 Hz, 3H), 2.53 (s, 1H), 2.33-2.01 (m, 5H). ESI-MS m/z calc.258.13437, found 259.2 (M+1)⁺;

B-207.(1S,3S)—N1-methyl-N1-(4-(trifluoromethyl)phenyl)cyclopentane-1,3-diaminehydrochloride

The compound was prepared in the same manner as B-204 and B-205 toprovide the product. 1H NMR (400 MHz, CD₃OD) δ 8.13 (d, J=8.5 Hz, 2H),7.97 (d, J=8.5 Hz, 2H), 4.77-4.65 (m, 1H), 4.02-3.86 (m, 1H), 3.36 (d,J=8.3 Hz, 3H), 2.65-2.35 (m, 2H), 2.24 (dd, J=62.9, 22.4 Hz, 3H), 1.83(ddt, J=13.3, 11.1, 7.8 Hz, 1H). ESI-MS m/z calc. 258.13437, found 259.2(M+1)⁺.

B-208.(1-((6-Fluoro-2-(prop-1-en-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminetrifluoroacetatic acid salt

The compound was prepared in the same manner as reported forintermediate B-81. ESI-MS m/z 247.13 (M+1)⁺.

B-209. cis-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diamine

A 4 M solution of HCl (22 ml, 88 mmol) in dioxane was added to asolution of tert-butyl(cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)carbamate (seeproduct for B-198, Step 1; 2 g, 5.89 mmol) in methanol (25 ml) andstirred at room temperature for 2 hours. The reaction was evaporated invacuo and the resulting solid was triturated with diethyl ether,filtered, and dried in vacuum oven at 50° C. to provide the titleproduct (1.98 g, 90% yield). 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d,J=1.2 Hz, 1H), 8.26 (s, 1H), 4.43-4.19 (m, 1H), 3.83-3.69 (m, 1H), 2.97(dtd, J=10.1, 7.3, 2.9 Hz, 2H), 2.39 (qt, J=8.9, 2.5 Hz, 2H). ESI-MS m/zcalc. 232.09358, found 233.13 (M+1)⁺.

B-210.cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-aminehydrochloride

The compound was prepared 2 steps in the same manner as B-197 to providethe title product. 1H NMR (300 MHz, CD₃OD) δ 7.77 (s, 1H), 6.59 (s, 1H),4.29 (d, J=7.1 Hz, 2H), 3.68 (p, J=8.2 Hz, 1H), 2.79-2.55 (m, 1H),2.53-2.37 (m, 2H), 1.99 (ddd, J=19.0, 9.5, 2.7 Hz, 2H). ESI-MS m/z found220.2 (M+1)⁺.

B-211.N-((cis-3-aminocyclobutyl)methyl)-5-(trifluoromethyl)pyrazin-2-aminedihydrochloride

The compound was in two steps in the same manner as B-197 to provide thetitle product. ¹H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J=1.3 Hz, 1H),8.03 (s, OH), 3.66 (s, 2H), 3.55-3.47 (m, 2H), 2.50 (d, J=6.5 Hz, 3H),1.94 (d, J=7.2 Hz, 2H). ESI-MS m/z calc. 246.10924, found 247.18 (M+1)⁺.

B-212.(1S,3R)—N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclopentane-1,3-diaminehydrochloride

The compound was prepared in a similar manner as B-197 to provide thetitle product. ¹H NMR (400 MHz, Methanol-d4) δ 8.26 (p, J=1.4 Hz, 2H),4.32 (q, J=6.9 Hz, 1H), 3.78-3.66 (m, 1H), 2.71 (dt, J=14.3, 7.5 Hz,1H), 2.20 (dddt, J=11.2, 9.2, 5.7, 3.3 Hz, 2H), 1.93 (tdd, J=10.5, 8.0,5.1 Hz, 2H), 1.75 (dt, J=13.5, 7.8 Hz, 1H).

B-213.(1S,3S)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)cyclobutan-1-amineStep 1: tert-butyl((1s,3s)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)-cyclobutyl)carbamate

To cis-tert-butyl N-[3-(hydroxymethyl)cyclobutyl]carbamate (5.8 g, 28.8mmol) and triphenylphosphane (9.1 g, 34.7 mmol) in THE (80 mL) at roomtemp was added diethylazodicarboxylate (15.8 mL of 40% w/w, 34.69 mmol),followed by 2-(trifluoromethyl)pyrimidin-5-ol (5.0 g, 30.5 mmol). Thereaction mixture was stirred at room temperature for 1 hour. THE wasremoved, added 100 mL dichloromethane, washed with 2 N NaOH twice. Theorganic phase was concentrated in vacuo. The resulting residue waspurified by silica gel chromatography using EtOAc/heptanes to afford8.17 grams of desired product: ¹H NMR (400 MHz, Chloroform-d) δ 8.51 (s,2H), 4.72 (s, 1H), 4.11 (d, J=5.5 Hz, 2H), 2.67-2.41 (m, 3H), 1.84-1.74(m, 1H).

Step 2:(1S,3S)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)cyclobutan-1-amine

To tert-butylN-[3-[[2-(trifluoromethyl)pyrimidin-5-yl]oxymethyl]cyclobutyl]carbamate,3, (8.17 g, 23.51 mmol) in Methanol (20 mL) was added hydrogen chloride(27 mL of 4 M solution, 108 mmol) in dioxane at room temperature. Stirat 50° C. for 30 minutes. The organics were evaporated and the resultingresidue was washed with ether-heptane to afford 6.5 g of desired productas HCl salt: ¹H NMR (300 MHz, Methanol-d4) δ 8.61 (s, 2H), 4.20 (d,J=5.5 Hz, 2H), 3.73 (tt, J=8.7, 7.6 Hz, 1H), 2.77-2.60 (m, 1H),2.57-2.40 (m, 2H), 2.24-1.94 (m, 2H); ESI-MS m/z calc. 247.09, found248.17 (M+1)⁺; Retention time: 0.58 minutes.

Example 2. Preparation of Compounds of the Invention 2A. Preparation ofCompounds of Table 4

Comp # L₁-Ring A R₁ R₂ R₃ R₄ R₆ Comp 53

H Me Me H Me Comp 1

Me Me Me H Me Comp 27

Me Me Me H H Comp 4

H Me Me H Me Comp 41

H Me Me H H Comp 22

Me Et Me H H Comp 19

Et Me Et H H Comp 32

Me i-Pr Et H H Comp 52

Et i-Pr Me H H Comp 24

Me Me n-Pr H H Comp 26

Me Me

H H Comp 20

Me Me

H H Comp 30

Et Et Me H H Comp 11

H H —(CH₂)₂—OH H H Comp 38

Et Et —(CH₂)₂—OH H H Comp 34

Et Et Et Me H Comp 221

H Me Spiro-c-Pr Me Comp 222

H H Spiro-c-Pr Me Comp 223

Me Me Spiro-c-Pr Me Comp 227

Me Me Spiro-c-Pr H Comp 232

Et Et Spiro-c-Pr H Comp 228

Me Me 3-Spiro-oxetane H Comp 224

Me Me Me Me H Comp 225

Me H Me Me H Comp 230

Et Et Me Me H Comp 9

H Me Et H H Comp 2

Me Me Me Et H Comp 3

Me Me Et Me H Comp 234

Et Et Me Et H Comp 69

H Me Me H Me Comp 55

H Me Me H Me Comp 71

H Me Me H Me Comp 72

H Me Me H Me Comp 149

H Me Me H Me Comp 147

H Me Me H H Comp 45

H Me Me H H Comp 49

Et Et CH₂CH₂OH H H Comp 47

H Me Me H Me Comp 68

H Me Me H Me Comp 78

H Me Me H Me Comp 79

H Me Me H H Comp 80

H Me Me H Me Comp 81

H Me Me H H Comp 14

Me Me Me H Me Comp 122

H Me Me H Me Comp 42

H Me Me H H Comp 229

Me Me Me Me H Comp 15

Me Me Et H H Comp 36

Me i-Pr Et H H Comp 33

Me CH₂CF₃ Et H H Comp 51

Et i-Pr Me H H Comp 31

Et Et Me H H Comp 231

Et Et Me Me H Comp 35

Et Et Et Me H Comp 235

Et Et Me Et H Comp 39

H H CH₂CH₂OH H H Comp 37

Et Et CH₂CH₂OH H H Comp 233

Et Et Spiro-c-Pr H Comp 23

Me Me n-Pr H H Comp 25

Me Me

H H Comp 21

Me Me

H H Comp 140

H Me Me H Me Comp 28

Me Me Me H Me Comp 141

H Me Me H H Comp 29

Me Me Me H Me Comp 65

H Me Me H Me Comp 66

H Me Me H Me Comp 67

H Me Me H Me Comp 17

Me Me Me H Me Comp 16

Me Me Me H Me Comp 18

Me Me Me H Me Comp 146

H Me Me H Me Comp 75

H Me Me H Me Comp 148

H Me Me H H Comp 181

H Me Me H Me Comp 83

H Me Me H Me Comp 84

Me Me Me H Me Comp 87

H Me Me H Me Comp 46

H Me Me H Me Comp 44

H Me Me H H Comp 48

Et Et —(CH₂)₂—OH H H Comp 88

H Me Me H Me Comp 63

Me Me Me H Me Comp 64

H Me Me H Me Comp 8

Me Me Me H Me Comp 6

H Me Me H Me Comp 13

H H —(CH₂)₂—OH H H Comp 123

H Me Me H Me Comp 103

H Me Me H Me Comp 109

H Me Me H H Comp 104

H Me Me H Me Comp 110

H Me Me H H Comp 105

H Me Me H Me Comp 111

H Me Me H H Comp 119

H Me Me H H Comp 106

H Me Me H Me Comp 121

H Me Me H H Comp 108

H Me Me H Me Comp 120

H Me Me H H Comp 107

H Me Me H Me Comp 112

H Me Me H Me Comp 137

H Me Me H Me Comp 113

H Me Me H Me Comp 115

H Me Me H Me Comp 58

H Me Me H Me Comp 5

H Me Me H Me Comp 7

Me Me Me H Me Comp 61

H Me Me H Me Comp 133

H Me Me H Me Comp 134

H Me Me H Me Comp 118

H Me Me H Me Comp 91

H Me Me H Me Comp 116

H Me Me H Me Comp 117

H Me Me H Me Comp 97

H Me Me H Me Comp 98

H Me Me H Me Comp 76

H Me Me H Me Comp 154

H Me Me H Me Comp 155

H Me Me H Me Comp 153

Me Me Me H Me Comp 152

Me Me Me H Me Comp 89

H Me Me H Me Comp 90

H Me Me H Me Comp 95

H Me Me H Me Comp 96

H Me Me H Me Comp 92

H Me Me H Me Comp 101

H Me Me H Me Comp 102

H Me Me H Me Comp 99

H Me Me H Me Comp 124

H Me Me H Me Comp 125

H Me Me H Me Comp 130

H Me Me H Me Comp 179

H Me Me H Me

A. General procedure for Method A Compound 46:(7S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-chloro-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one (9.4 g, 41.5mmol) and(1-(3,5-difluoro-4-methoxy-5-methylbenzyl)-1H-pyrazol-4-yl)methanaminehydrochloride (13.8 g, 42.3 mmol) were taken into 170 ml of t-butanoland degassed with nitrogen. Sodium t-butoxide (13.94 g, 145 mmol) wasadded to the mixture followed by the addition of t-BuXPhos palladium(II)phenethylamine chloride (also know as tBuXPhos Pd Gen 1) (570 mg, 0.83mmol). The reaction was purged with nitrogen for 5 minutes, then heatedto 50° C. for 2 hours. The solvent was evaporated in vacuo and water(200 ml) was added to the residue and extracted with dichloromethane(2×200 ml). The combined organic extracts were washed with brine, driedover anhydrous sodium sulfate, filtered, and evaporated to afford thecrude product. The crude product was purified by column chromatography(330 g SiO) eluting with a gradient of 0-20% methanol indichloromethane. The desired fractions were combined and evaporated invacuo to afford a green solid. The green solid was dissolved indichloromethane (100 ml) and 4.5 g of Biotage MP-TMT resin was stirredat room temperature for 16 hours (to remove Pd). The solvent wasfiltered through Florosil and Celite to obtain a clear colorlesssolution. The filtrate was evaporated in vacuo to afford a white foam.Heptane was added to the residue and stirred for 1 hour. The resultingmaterial was collected by vacuum filtration and dried in a vacuum ovenat 50° C. for 20 hours to provide the title product, wt. 15 g (80.7%yield). 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.68 (s, 1H), 7.40 (d,J=0.5 Hz, 1H), 7.06-6.87 (m, 2H), 6.60 (t, J=5.9 Hz, 1H), 5.21 (s, 2H),4.22 (d, J=6.0 Hz, 2H), 4.00 (q, J=6.8 Hz, 1H), 3.88 (t, J=0.9 Hz, 3H),2.94 (s, 3H), 2.13 (s, 3H), 1.18 (d, J=6.8 Hz, 3H); F19 NMR δ−128.50,−128.53 ppm; ESMS (M+1)=444.28. mp=136-138° C. Chiral HPLC (AD-H column;40% isopropanol/60% hexane/0.1% diethylamine) Rt=8.906 mins. (98% ee);[α]_(D)=44.020 (c=1, methanol).

B. General Procedure for Method B Compound 1:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-Chloro-4,5,7,8-tetramethyl-7H-pteridin-6-one (90 g, 373.9 mmol)and (1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methanamine hydrochloride (108.4g, 448.7 mmol) was taken into n-butanol (1.35 L) and heated at refluxfor 20 hours under nitrogen. The solvent was removed in vacuo. Theresulting residue was taken into saturated sodium bicarbonate (1 L) andextracted with ethyl acetate (1.5 L). The aqueous was extracted furtherwith ethyl acetate (1 L). The extracts were combined, washed with brine,dried over anhydrous sodium sulfate, filtered, and evaporated in vacuoto afford the crude product. The crude was purified by columnchromatography (SiO₂) eluting with a gradient of 0-100% acetone inhexanes. The desired fractions were combined and evaporated in vacuo.tert-Butyl methyl ether (500 ml) and heptane (200 ml) was added to theevaporated material. The title product was obtained by subsequent vacuumfiltration followed by washing with t-Butyl methyl ether, then drying ina vacuum oven at 50° C. overnight, wt. 59 g (38.1% yield). 1H NMR (300MHz, CD₃OD) δ 7.60 (s, 1H), 7.48 (s, 1H), 7.22 (dd, J=8.5, 5.4 Hz, 2H),7.03 (t, J=8.8 Hz, 2H), 5.25 (s, 2H), 4.39 (s, 2H), 4.03 (q, J=6.9 Hz,1H), 3.27 (s, 3H), 3.00 (s, 3H), 2.32 (s, 3H), 1.15 (d, J=6.9 Hz, 3H);F19 NMR δ 118.04 ppm; ESMS (M+1)=410.36 mins. Chiral HPLC (IA column;40% ethanol/60% hexane, isocratic), Rt=12.775 mins; [α]_(D)=20.2° (c=1,methanol).

Compound 53.(7S)-2-(((1-benzyl-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediate A-2 and (1-benzyl-1H-pyrazol-4-yl)methanamine hydrochlorideto provide the title compound; Yield 41%; 1H NMR (300 MHz, Methanol-d4)δ 7.85 (s, 1H), 7.68 (s, 1H), 7.28-7.18 (m, 3H), 7.18-7.10 (m, 2H), 5.29(s, 2H), 4.43 (s, 2H), 4.18 (q, J=6.8 Hz, 1H), 3.08 (s, 3H), 2.19 (s,3H), 1.40 (d, J=6.9 Hz, 3H); ESMS (M+H)=378.34.

Compound 27:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-35 and B-2 to provide the title compound; Yield 78%: 1HNMR (300 MHz, CDCl3) δ 7.44 (s, 2H), 7.28 (s, 1H), 7.11 (dd, J=8.5, 5.4Hz, 2H), 6.94 (t, J=8.6 Hz, 2H), 5.13 (d, J=10.9 Hz, 2H), 4.96 (d,J=27.5 Hz, 1H), 4.32 (t, J=7.4 Hz, 2H), 4.05 (q, J=6.8 Hz, 1H), 3.18 (s,3H), 2.94 (s, 3H), 1.29 (d, J=6.8 Hz, 3H); ESMS (M+H)=396.14.

Compound 4:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-2 to provide the title compound; Yield 68.8%; 1HNMR (300 MHz, CDCl₃) δ 8.07 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.20(dd, J=8.7, 5.3 Hz, 2H), 7.04 (t, J=8.7 Hz, 2H), 5.24 (s, 2H), 4.81 (t,J=5.5 Hz, 1H), 4.42 (d, J=5.7 Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.04 (s,3H), 2.22 (s, 3H), 1.40 (d, J=6.9 Hz, 3H); ESMS (M+H)=396.32; ChiralHPLC (AD-H column; 40% isopropanol/60% hexanes (0.1% diethylamine,isocratic): Rt 7.018 mins. (98% ee); [α]_(D) ²⁰+44.80 (c=1, methanol).

Compound 41:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-1 and B-2 to provide the title compound; Yield 62% 1HNMR (300 MHz, CDCl₃) δ 7.63-7.48 (m, 3H), 7.29-7.17 (m, 2H), 7.09-6.97(m, 2H), 5.26 (s, 2H), 4.48 (d, J=5.4 Hz, 2H), 4.23 (q, J=6.9 Hz, 1H),3.21 (s, 3H), 1.58 (d, J=6.9 Hz, 3H); ESMS (M+H)=382.31.

Compound 22:(7S)-8-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-24 and B-2 to provide the title compound; Yield 62% 1HNMR (300 MHz, CDCl₃) δ 7.45 (d, J=4.9 Hz, 2H), 7.27 (s, 1H), 7.16-7.09(m, 2H), 7.02-6.89 (m, 2H), 5.15 (s, 2H), 4.93 (t, J=5.1 Hz, 1H), 4.32(t, J=7.3 Hz, 2H), 4.09 (dd, J=14.4, 7.6 Hz, 1H), 3.93 (dq, J=14.4, 7.2Hz, 1H), 3.18 (s, 3H), 3.01 (tt, J=12.2, 6.1 Hz, 1H), 1.28 (d, J=6.8 Hz,3H), 1.16-1.06 (m, 3H); ESMS (M+H)=410.23.

Compound 19:(7S)-5,7-Diethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-43 and B-2 to provide the title compound; ¹H NMR (300MHz, CDCl₃) δ δ 7.51 (s, 2H), 7.34 (d, J=0.8 Hz, 1H), 7.23-7.11 (m, 2H),7.00 (t, J=8.7 Hz, 1H), 5.21 (s, 2H), 4.90 (t, J=5.7 Hz, 1H), 4.40 (d,J=5.7 Hz, 2H), 4.08 (dd, J=6.0, 3.7 Hz, 1H), 3.97 (dq, J=14.3, 7.2 Hz,1H), 3.77 (dq, J=14.2, 7.1 Hz, 1H), 3.01 (s, 3H), 1.95 (dtt, J=15.0,7.5, 3.7 Hz, 1H), 1.79 (dqd, J=14.7, 7.4, 5.9 Hz, 1H), 1.22 (t, J=7.2Hz, 3H), 0.79 (t, J=7.5 Hz, 3H); ESMS (M+1)=424.23.

Compound 32:(7S)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-18 and B-2 to provide the title compound; 46% yield. 1HNMR (300 MHz, CDCl₃) δ 7.44 (s, 2H), 7.27 (s, 1H), 7.17-7.09 (m, 2H),7.00-6.89 (m, 2H), 5.15 (s, 2H), 4.96 (s, 1H), 4.44 (dt, J=13.7, 6.8 Hz,1H), 4.34 (d, J=5.6 Hz, 2H), 4.13 (dd, J=7.6, 3.4 Hz, 1H), 3.20 (s, 3H),1.81 (dtt, J=15.1, 7.5, 3.8 Hz, 1H), 1.69-1.57 (m, 1H), 1.25 (t, J=6.5Hz, 6H), 0.78 (t, J=7.5 Hz, 3H); ESMS (M+1)=438.32.

Compound 52:(7S)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-19 and B-2 to provide the title compound; 47% yield. 1HNMR (300 MHz, CDCl₃) δ 7.52 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H),7.15-7.06 (m, 2H), 6.98-6.88 (m, 2H), 5.15 (s, 2H), 5.01 (t, J=5.1 Hz,1H), 4.54 (hept, J=6.8 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H), 4.24-4.08 (m,1H), 3.93-3.76 (m, 1H), 3.68 (dq, J=14.2, 7.1 Hz, 1H), 2.62 (s, 1H),1.29-1.07 (m, 12H); ESMS (M+1)=438.32

Compound 24:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,8-dimethyl-7-propyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-50 and B-2 to provide the title compound; 1H NMR (300MHz, Methanol-d4) δ 7.61 (d, J=0.8 Hz, 1H), 7.53-7.44 (m, 2H), 7.28-7.17(m, 2H), 7.10-6.97 (m, 2H), 5.25 (s, 2H), 4.37 (s, 2H), 4.19 (dd, J=5.7,4.2 Hz, 1H), 3.26 (s, 3H), 3.05 (s, 3H), 1.90-1.70 (m, 2H), 1.18 (dtt,J=9.1, 7.3, 6.0 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H); ESMS (M+1)=424.23Compound 26:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,8-dimethyl-7-(prop-2-yn-1-yl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-10 and B-2 to provide the title compound; 5% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.76 (d, J=0.8 Hz, 1H), 7.57 (d, J=0.8 Hz,1H), 7.42 (s, 1H), 7.33-7.22 (m, 2H), 7.12-7.00 (m, 2H), 5.29 (s, 2H),4.62-4.49 (m, 3H), 3.28 (d, J=7.8 Hz, 6H), 3.05 (ddd, J=17.7, 4.8, 2.7Hz, 1H), 2.90 (dt, J=17.7, 2.8 Hz, 1H); ESMS (M+1)=420.22

Compound 20:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-((R)-1-methoxyethyl)-5,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-20 and B-2 to provide the title compound; 1H NMR (300MHz, Methanol-d4) δ 7.78-7.66 (m, 2H), 7.58-7.50 (m, 1H), 7.42-7.21 (m,2H), 7.05 (t, J=8.7 Hz, 2H), 5.28 (s, 2H), 4.51 (s, 2H), 4.44-4.22 (m,1H), 3.90-3.66 (m, 1H), 3.29-3.14 (m, 9H), 1.32-1.13 (m, 3H); ESMS(M+1)=440.21.

Compound 30:(7S)-5,8-diethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-22 and B-2 to provide the title compound; 44% yield. 1HNMR (300 MHz, CDCl₃) δ 7.48 (s, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.27 (s,1H), 7.15-7.06 (m, 2H), 6.99-6.88 (m, 2H), 5.15 (s, 2H), 4.95 (dd,J=17.0, 3.5 Hz, 1H), 4.32 (t, J=7.3 Hz, 2H), 4.19-3.60 (m, 4H),3.14-2.92 (m, 1H), 1.25 (t, J=6.9 Hz, 3H), 1.14 (dt, J=14.2, 5.4 Hz,6H); ESMS (M+H)=424.27.

Compound 11:(7S)-2-(((1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-25 and B-2 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.77 (d, J=4.4 Hz, 1H), 7.60 (d, J=2.6 Hz, 1H),7.32-7.13 (m, 3H), 7.06 (t, J=8.7 Hz, 2H), 5.30 (s, 2H), 4.63-4.41 (m,3H), 3.81-3.68 (m, 2H), 2.45-2.01 (m, 2H); ESMS (M+1)=398.24.

Compound 38:(7S)-5,8-diethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-26 and B-2 to provide the title compound; 14% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.84 (s, 1H), 7.70 (t, J=1.0 Hz, 1H),7.56-7.48 (m, 1H), 7.32-7.21 (m, 2H), 7.11-6.99 (m, 2H), 5.28 (s, 2H),4.66-4.34 (m, 5H), 4.22-3.77 (m, 4H), 2.52-2.26 (m, 2H), 1.32-1.12 (m,6H); ESMS (M+H)=454.43.

Compound 34:(7S)-5,7,8-triethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-30 and B-2 to provide the title compound; 43% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.16 (s, 1H), 7.54 (s, 1H),7.43 (dd, J=8.6, 5.2 Hz, 2H), 7.21-7.08 (m, 2H), 5.56 (s, 2H), 4.63 (d,J=2.8 Hz, 2H), 3.99 (dt, J=14.0, 7.0 Hz, 1H), 3.82 (tq, J=14.0, 6.9 Hz,2H), 3.52 (dq, J=13.9, 6.9 Hz, 1H), 3.31 (dt, J=3.3, 1.6 Hz, 1H),2.16-1.92 (m, 2H), 1.70 (s, 3H), 1.20 (m, 6H), 0.76 (t, J=7.4 Hz, 3H);ESMS (M+H)=452.27.

Compound 221:2′-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-16 and B-2 to provide the title compound; 17% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.67 (s, 1H), 7.49 (s, 1H), 7.23 (dd,J=8.5, 5.5 Hz, 2H), 7.03 (t, J=8.7 Hz, 2H), 5.25 (s, 2H), 4.46 (s, 2H),2.94 (s, 3H), 2.24 (s, 3H), 1.61 δ 1.37 (m, 4H); ESMS (M+H)=408.42.

Compound 222:2′-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4′-methyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by the general procedure Method B via reactionof intermediates A-53 and B-2 to provide the title compound; 23% yield.1H NMR (300 MHz, Methanol-d4) δ 8.02 (s, 1H), 7.82 (d, J=6.0 Hz, 1H),7.20 (dt, J=8.7, 5.9 Hz, 2H), 7.06-6.92 (m, 2H), 5.34 (s, 2H), 4.33 (s,2H), 2.13 (s, 3H), 1.45 (dd, J=8.0, 4.9 Hz, 2H), 1.03 (dd, J=8.0, 5.0Hz, 2H); ESMS (M+1)=394.38.

Compound 223:2′-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4′,5′,8′-trimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-33 and B-2 to provide the title compound; 32% yield. 1HNMR (300 MHz, DMSO-d6) δ 12.78 (br.s, 1H), 7.97 (br.s, 1H), 7.78 (s,1H), 7.45 (s, 1H), 7.32-7.24 (m, 2H), 7.21-7.12 (m, 2H), 5.27 (s, 2H),4.40 (d, J=5.7 Hz, 2H), 3.40 (br.s, 1H), 3.23 (s, 3H), 2.98 (s, 3H),2.40 (s, 3H), 1.52-1.43 (m, 2H), 1.34-1.26 (m, 2H); ESMS (M+H)=422.18.

Compound 227:2′-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-36 and B-2 to provide the title compound; 25% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.13 (d, J=13.9 Hz, 1H), 7.94 (s, 1H),7.47-7.30 (m, 3H), 7.21-6.99 (m, 2H), 5.46 (s, 2H), 4.56 (s, 2H), 3.23(s, 3H), 2.96 (d, J=10.3 Hz, 3H), 1.63-1.54 (m, 4H); ESMS (M+H)=408.2.

Compound 232:5′,8′-diethyl-2′-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-37 and B-2 to provide the title compound; 79% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.26 (s, 1H), 8.10 (s, 1H), 7.47 (s, 1H),7.45-7.35 (m, 2H), 7.19-7.08 (m, 2H), 5.54 (s, 2H), 4.60 (s, 2H), 3.85(q, J=7.1 Hz, 2H), 3.39 (q, J=6.9 Hz, 2H), 1.65-1.44 (m, 4H), 1.20 (q,J=7.5 Hz, 3H), 1.10 (t, J=7.0 Hz, 3H); ESMS (M+H)=436.25.

Compound 228:2′-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dimethyl-5′,8′-dihydro-6′H-spiro[oxetane-3,7′-pteridin]-6′-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-52 and B-2 to provide the title compound, 40% yield). 1HNMR (300 MHz, CDCl₃) δ 7.44 (d, J=3.5 Hz, 2H), 7.28 (s, 1H), 7.17-7.07(m, 2H), 7.03-6.88 (m, 2H), 5.21 (t, J=7.2 Hz, 2H), 5.14 (s, 2H), 4.76(t, J=8.3 Hz, 2H), 4.35 (d, J=5.7 Hz, 2H), 3.40 (s, 3H), 3.23 (s, 3H);ESMS (M+1)=424.23.

Compound 224:2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-14 and B-2 to provide the title compound; 27% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H),7.36 (s, 2H), 7.11 (t, J=8.1 Hz, 2H), 5.46 (s, 2H), 4.58 (s, 2H), 3.26(s, 3H), 3.24 (s, 3H), 1.68 (d, J=14.7 Hz, 6H); ESMS (M+H)=409.89.

Compound 225:2-(((1-(4-Fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7,7-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-54 and B-2 to provide the title compound; 55% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.99 (s, 1H), 7.81 (s, 1H), 7.43 (s, 1H),7.31 (dd, J=8.5, 5.3 Hz, 2H), 7.08 (td, J=8.7, 4.7 Hz, 2H), 5.39 (s,2H), 4.49 (s, 2H), 3.26 (d, J=6.4 Hz, 3H), 1.56 (s, 6H); ESMS(M+1)=395.89.

Compound 230:5,8-diethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,7-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-15 and B-2 to provide the title compound; 61% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.28 (s, 1H), 7.56 (s, 1H),7.47 (dd, J=8.6, 5.3 Hz, 2H), 7.15 (t, J=8.7 Hz, 2H), 5.63 (s, 2H), 4.65(s, 2H), 3.88 (q, J=7.1 Hz, 2H), 3.73 (q, J=6.9 Hz, 2H), 1.64 (s, 6H),1.18 (dt, J=9.4, 7.1 Hz, 6H); ESMS (M+H)=438.27.

Compound 9:(7S)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-methyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-41 and B-2 to provide the title compound; 61% yield. ¹HNMR (300 MHz, CDCl₃) δ 7.65 (s, 1H), 7.48 (d, J=0.7 Hz, 1H), 7.25-7.15(m, 2H), 7.13 (s, 1H), 6.99 (t, J=8.8 Hz, 2H), 5.22 (s, 2H), 4.43 (s,2H), 4.30 (dd, J=5.3, 3.4 Hz, 1H), 3.16 (s, 3H), 2.10-1.85 (m, 2H), 0.78(t, J=7.5 Hz, 3H); ESMS (M+H)=396.18. Analytical SFC (AD-H column; 45%Methanol (0.2% diethylamine)/55% CO2; isocractic): Rt 6.12 mins. (99%ee); [α]_(D)=26.7° (c=1, DMSO).

Compound 2:(7S)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-32 and B-2 to provide the title product; 44%. 1H NMR(300 MHz, CDCl₃) δ 7.48 (d, J=7.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H),7.17 (dd, J=8.4, 5.4 Hz, 2H), 6.99 (t, J=8.6 Hz, 2H), 5.20 (s, 2H), 5.09(s, 1H), 4.39 (d, J=5.5 Hz, 2H), 3.27 (s, 3H), 2.98 (s, 3H), 2.16 (dq,J=14.7, 7.4 Hz, 1H), 1.72 (tt, J=12.4, 6.2 Hz, 1H), 0.76 (t, J=7.3 Hz,3H); ESMS (M+H)=424.27.

Compound 3:(7R)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-31 and B-2 to provide the title product; 45%. 1H NMR(300 MHz, CDCl₃) δ 7.53 (s, 1H), 7.47 (s, 1H), 7.36 (s, 1H), 7.20 (dd,J=8.4, 5.4 Hz, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.23 (s, 2H), 4.96 (d,J=22.6 Hz, 1H), 4.41 (d, J=5.6 Hz, 2H), 3.28 (s, 3H), 3.01 (d, J=7.4 Hz,3H), 2.19 (td, J=14.7, 7.4 Hz, 1H), 1.76 (dq, J=14.5, 7.3 Hz, 1H), 0.80(t, J=7.3 Hz, 3H); ESMS (M+H)=424.32.

Compound 234:(7R)-5,7,8-triethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-methyl-7,8-dihydropteridin-6(5H)-one

The compound This compound was made in a similar manner as describedabove using intermediates A-28 and B-2. 1H NMR (300 MHz, CDCl₃) δ 7.44(d, J=3.5 Hz, 2H), 7.28 (s, 1H), 7.17-7.07 (m, 2H), 7.03-6.88 (m, 2H),5.21 (t, J=7.2 Hz, 2H), 5.14 (s, 2H), 4.76 (t, J=8.3 Hz, 2H), 4.35 (d,J=5.7 Hz, 2H), 3.40 (s, 3H), 3.23 (s, 3H); ESMS (M+1)=424.23.

Compound 69:(7S)-2-(((1-(3-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-3 to provide the title product; 76% yield. 1HNMR (300 MHz, CDCl₃) δ 8.16 (s, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.41-7.24(m, 3H), 7.07-6.93 (m, 2H), 6.92-6.82 (m, 1H), 5.27 (s, 2H), 4.85 (t,J=5.7 Hz, 1H), 4.43 (d, J=5.7 Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.04 (s,3H), 2.23 (s, 3H), 1.40 (d, J=6.8 Hz, 3H); ESMS (M+H)=396.23; [α]_(D)²⁰+45.0° (c=1, methanol).

Compound 55:(7S)-4-((4-(((4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzonitrile

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-8 to provide the title product; 49% yield. 1HNMR (300 MHz, CDCl₃) δ 7.77 (s, 1H), 7.73-7.64 (m, 2H), 7.57 (s, 1H),7.34 (d, J=8.0 Hz, 2H), 5.41 (s, 2H), 4.52 (s, 2H), 4.30 (q, J=6.9 Hz,1H), 3.23 (s, 3H), 2.28 (s, 4H), 1.52 (d, J=6.9 Hz, 3H); ESMS(M+H)=403.18. [α]_(D)=14.2° (c=1, DMSO).

Compound 382:(7S)-2-(((1-(1-(4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-4 to afford the title product as a mixture ofdiastereomers. The diastereomers were separated by SFC chromatography(Whelk-02, 10×250 mm column; 40% MeOH (0.2% Et₂N), 60% CO2, isocratic;15 ml/min) and assigned as diastereomer A (Rt 5.337 mins) and B (Rt7.164 mins) Compound 71:(7S)-2-(((1-((S)-1-(4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.58 (s, 1H), 7.29 (dd,J=8.6, 5.4 Hz, 2H), 7.08 (t, J=8.7 Hz, 2H), 5.62-5.50 (m, 1H), 4.53 (s,2H), 4.33 (dd, J=13.9, 6.9 Hz, 1H), 3.25 (s, 3H), 2.31 (s, 3H), 1.88 (d,J=7.1 Hz, 3H), 1.55 (d, J=6.9 Hz, 3H); ESMS (M+H)=410.27. Analytical SFCchromatography (Whelk-02 column, 4.6×100 mm; 40% MeOH (0.2% Et₂N), 60%CO₂, isocratic; 5 ml/min): Rt 5.053 mins. (97.4% de).

Compound 72:(7S)-2-(((1-((R)-1-(4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.58 (s, 1H), 7.29 (dd,J=8.6, 5.4 Hz, 2H), 7.08 (t, J=8.7 Hz, 2H), 5.62-5.50 (m, 1H), 4.53 (s,2H), 4.33 (dd, J=13.9, 6.9 Hz, 1H), 3.25 (s, 3H), 2.31 (s, 3H), 1.88 (d,J=7.1 Hz, 3H), 1.55 (d, J=6.9 Hz, 3H); ESMS (M+1)=410.31. Analytical SFCchromatography (Whelk-02 column, 4.6×100 mm; 40% MeOH (0.2% Et₂N), 60%CO₂, isocratic; 5 ml/min): Rt 6.505 mins. (99.2% de).

Compound 149:(7S)-4,7,8-trimethyl-2-(((1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-5 to provide the title product; 48% yield. 1HNMR (300 MHz, CDCl₃) δ 8.14 (s, 1H), 7.66-7.52 (m, 3H), 7.40 (d, J=0.8Hz, 1H), 7.35-7.28 (m, 2H), 5.33 (s, 2H), 4.96 (s, 1H), 4.44 (d, J=5.7Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.05 (s, 3H), 2.24 (s, 3H), 1.41 (d,J=6.9 Hz, 3H); ESMS (M+H)=446.17.

Compound 147:(7S)-7,8-dimethyl-2-(((1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-5 to provide the title product; 48% yield. 1HNMR (300 MHz, CDCl₃) δ 7.55-7.46 (m, 3H), 7.40-7.33 (m, 1H), 7.26-7.16(m, 3H), 5.24 (s, 2H), 4.38 (d, J=5.7 Hz, 2H), 3.96 (q, J=6.8 Hz, 1H),2.98 (s, 3H), 1.35 (d, J=6.9 Hz, 3H); ESMS (M+H)=432.35.

Compound 45:(7S)-7,8-dimethyl-2-(((1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-1 and B-6 to provide the title product; 48% yield. 1HNMR (300 MHz, CDCl₃) δ 7.63-7.35 (m, 7H), 5.33 (s, 2H), 4.48 (d, J=5.6Hz, 2H), 4.17 (q, J=6.9 Hz, 1H), 3.16 (s, 3H), 1.54 (d, J=7.0 Hz, 3H);ESMS (M+H)=432.27.

Compound 49:(7S)-5,8-diethyl-7-(2-hydroxyethyl)-2-(((1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-26 and B-6 to provide the title product; 14% yield. 1HNMR (300 MHz, CDCl₃) δ 7.66-7.35 (m, 7H), 5.34 (s, 2H), 4.46 (d, J=5.8Hz, 2H), 4.32 (dd, J=9.0, 4.1 Hz, 1H), 4.07 (ddt, J=39.0, 14.3, 7.1 Hz,2H), 3.84-3.61 (m, 3H), 3.11 (dt, J=14.1, 7.1 Hz, 1H), 2.13 (dt, J=8.3,4.5 Hz, 1H), 1.82 (tt, J=9.2, 4.7 Hz, 1H), 1.24 (td, J=7.1, 6.0 Hz, 6H);ESMS (M+H)=504.28.

Compound 47:(7S)-4,7,8-trimethyl-2-(((1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-6 to provide the title product; 65% yield. 1HNMR (300 MHz, CDCl₃) δ 7.61-7.32 (m, 6H), 5.33 (s, 2H), 4.83 (s, 1H),4.45 (s, 2H), 4.45-3.70 (m, 1H), 3.04 (s, 3H), 2.20 (s, 3H), 1.41 (d,J=6.8 Hz, 3H); ESMS (M+H)=446.28; [α]_(D) ²⁰+49.20 (c=1, methanol).

Compound 68:(7S)-4,7,8-trimethyl-2-(((1-(2-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-7 to provide the title product; 48% yield. 1HNMR (300 MHz, CDCl₃) δ 7.69 (d, J=7.7 Hz, 1H), 7.58 (s, 1H), 7.52-7.37(m, 3H), 6.98 (d, J=7.6 Hz, 1H), 5.50 (s, 2H), 4.44 (d, J=5.7 Hz, 2H),4.08 (q, J=6.8 Hz, 1H), 3.05 (s, 3H), 2.23 (s, 3H), 1.41 (d, J=6.8 Hz,3H); ESMS (M+H)=446.24.

Compound 78:(7S)-2-(((1-(2-isopropylbenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-9 to provide the title product; 45% yield. 1HNMR (300 MHz, CDCl₃) δ 7.53 (d, J=0.8 Hz, 1H), 7.39-7.31 (m, 2H),7.25-7.13 (m, 2H), 7.13-7.03 (m, 1H), 5.35 (s, 2H), 4.79 (s, 1H), 4.38(d, J=5.7 Hz, 2H), 4.07 (q, J=6.8 Hz, 1H), 3.16 (p, J=6.8 Hz, 1H), 3.02(s, 3H), 2.19 (s, 3H), 1.40 (d, J=6.9 Hz, 3H), 1.19-1.10 (m, 6H); ESMS(M+H)=420.33.

Compound 79:(7S)-2-(((1-(2-isopropylbenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-9 to provide the title product; 48% yield. 1HNMR (300 MHz, CDCl₃) δ 7.58-7.51 (m, 1H), 7.41-7.30 (m, 3H), 7.27-7.03(m, 3H), 5.34 (s, 2H), 4.40 (d, J=5.8 Hz, 2H), 4.06 (q, J=6.8 Hz, 1H),3.16 (p, J=6.8 Hz, 1H), 3.03 (s, 3H), 1.44 (d, J=6.9 Hz, 3H), 1.14 (d,J=6.8 Hz, 6H); ESMS (M+H)=406.23.

Compound 80:(7S)-2-(((1-(3-isopropylbenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-10 to provide the title product; 62% yield. 1HNMR (300 MHz, CDCl₃) δ 7.57 (d, J=18.7 Hz, 2H), 7.38-7.15 (m, 2H), 7.10(s, 1H), 7.02 (d, J=7.5 Hz, 1H), 5.26 (s, 2H), 4.81 (d, J=6.4 Hz, 1H),4.42 (d, J=5.7 Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.05 (s, 3H), 2.90 (p,J=6.9 Hz, 1H), 2.21 (s, 3H), 1.41 (d, J=6.8 Hz, 3H), 1.25 (d, J=6.9 Hz,6H); ESMS (M+H)=420.28.

Compound 81:(7S)-2-(((1-(3-isopropylbenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-10 to provide the title product; 60% yield. 1HNMR (300 MHz, CDCl₃) δ 7.55 (d, J=0.8 Hz, 1H), 7.44-7.34 (m, 2H),7.33-6.98 (m, 4H), 5.26 (s, 2H), 4.44 (d, J=5.8 Hz, 2H), 4.08 (q, J=6.8Hz, 1H), 3.06 (s, 3H), 2.89 (p, J=6.9 Hz, 1H), 1.45 (d, J=6.9 Hz, 3H),1.24 (d, J=6.9 Hz, 6H); ESMS (M+H)=406.32.

Compound 14:(7S)-4,5,7,8-tetramethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-23 to provide the title product; 31% yield. 1HNMR (300 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.43 (s, 1H), 7.13 (dd, J=8.7,6.8 Hz, 2H), 6.86 (t, J=5.6 Hz, 1H), 5.27 (s, 2H), 4.34-4.16 (m, 2H),4.02 (q, J=6.8 Hz, 1H), 3.18 (s, 3H), 2.92 (s, 3H), 2.27 (s, 3H), 1.05(d, J=6.8 Hz, 3H); ESMS (M+H)=446.31; [α]_(D) ²⁰+23.4σ (c=1, methanol).

Compound 122:(7S)-4,7,8-trimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-23 to provide the title product; 44% yield. 1HNMR (300 MHz, CDCl₃) δ 8.72 (s, 1H), 7.55 (s, 1H), 7.39 (s, 1H), 6.79(t, J=7.0 Hz, 2H), 5.20 (s, 2H), 4.90 (t, J=5.9 Hz, 1H), 4.44 (d, J=5.8Hz, 2H), 4.07 (q, J=6.8 Hz, 1H), 3.05 (s, 3H), 2.25 (s, 3H), 1.40 (d,J=6.9 Hz, 3H); ESMS (M+H)=432.15.

Compound 42:(7S)-7,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-23 to provide the title product; 65% yield. 1HNMR (400 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H),6.92 (dd, J=8.5, 6.6 Hz, 2H), 5.26 (s, 2H), 4.38 (s, 2H), 4.11 (q, J=6.9Hz, 1H), 3.05 (s, 3H), 1.38 (d, J=6.9 Hz, 3H); ESMS (M+H)=418.29;[α]_(D) ²⁰+39.2° (c=1.04, DMSO).

Compound 229:5,7,7,8-tetramethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-14 and B-23 to provide the title product; 91% yield. 1HNMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 8.40 (s, 1H), 7.87 (s, 1H), 7.59(s, 1H), 7.52 (s, 1H), 7.16 (dd, J=8.8, 6.8 Hz, 2H), 5.31 (s, 2H), 4.44(d, J=5.7 Hz, 2H), 3.19 (d, J=4.2 Hz, 3H), 3.17 (s, 3H), 1.57 (s, 6H);ESMS (M+H)=446.4.

Compound 15:(7S)-7-Ethyl-5,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction by general procedure Method B viareaction of intermediates A-42 and B-23 to provide the title product. ¹HNMR (300 MHz, CDCl₃) δ 1H) δ 7.65 (s, 1H), 7.44 (s, 1H) 7.28 (s, 1H),6.92-6.68 (m, 2H), 5.15 (s, 2H), 4.39 (s, 2H), 4.29 (dd, J=5.4, 3.4 Hz,1H), 3.12 (s, 4H), 3.11 (s, 4H), 1.91 (pd, J=7.3, 4.4 Hz, 2H), 0.64 (t,J=7.4 Hz, 3H); ESMS (M+1)=446.19.

Compound 36:(7S)-7-ethyl-8-isopropyl-5-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-18 and B-23 to provide the title product; 388% yield. 1HNMR (300 MHz, CDCl₃) δ 7.46 (d, J=4.2 Hz, 1H), 7.45 (s, 1H), 7.32 (s,1H), 6.76-6.67 (m, 2H), 5.12 (s, 2H), 5.01 (s, 1H), 4.45 (dt, J=13.1,6.5 Hz, 1H), 4.37 (d, J=5.7 Hz, 2H), 4.14 (dd, J=7.6, 3.4 Hz, 1H), 3.20(s, 3H), 1.90-1.74 (m, 1H), 1.73-1.54 (m, 1H), 1.31-1.21 (m, 6H), 0.78(t, J=7.5 Hz, 3H); ESMS (M+H)=474.28.

Compound 33:(7S)-7-ethyl-5-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-(2,2,2-trifluoroethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-45 and B-23 to provide the title product; 30.4% yield.1H NMR (300 MHz, Methanol-d4) δ 7.98 (d, J=9.7 Hz, 1H), 7.81 (s, 1H),7.68 (s, 1H), 7.04 (td, J=7.9, 5.0 Hz, 2H), 5.38 (d, J=11.1 Hz, 2H),5.16-5.02 (m, 1H), 4.71-4.50 (m, 2H), 4.17 (dt, J=17.4, 8.6 Hz, 1H),3.31 (d, J=1.1 Hz, 5H), 2.10-1.90 (m, 3H), 0.86 (t, J=7.4 Hz, 3H); ESMS(M+1)=514.12.

Compound 51:(7S)-5-ethyl-8-isopropyl-7-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-19 and B-23 to provide the title product; 80% yield. 1HNMR (300 MHz, CDCl₃) δ 7.54 (s, 1H), 7.45 (d, J=10.6 Hz, 1H), 7.33 (s,1H), 6.76-6.67 (m, 2H), 5.12 (s, 2H), 5.00 (t, J=5.5 Hz, 1H), 4.54 (dq,J=13.2, 6.6 Hz, 1H), 4.35 (t, J=5.8 Hz, 2H), 4.18 (q, J=6.7 Hz, 1H),3.87 (dq, J=14.3, 7.1 Hz, 1H), 3.77-3.58 (m, 1H), 1.19 (m, 12H); ESMS(M+H)=474.37.

Compound 31:(7S)-5,8-diethyl-7-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-22 and B-23 to provide the title product; 75% yield. 1HNMR (300 MHz, CDCl₃) δ 7.49 (d, J=5.9 Hz, 1H), 7.45 (d, J=10.3 Hz, 1H),7.33 (s, 1H), 6.77-6.67 (m, 2H), 5.12 (s, 2H), 4.97 (d, J=5.2 Hz, 1H),4.36 (d, J=5.6 Hz, 2H), 4.10 (q, J=6.8 Hz, 1H), 4.00-3.62 (m, 3H), 3.04(dq, J=14.1, 7.1 Hz, 1H), 1.26 (t, J=7.7 Hz, 3H), 1.14 (dd, J=13.5, 7.1Hz, 6H); ESMS (M+H)=460.28.

Compound 231:5,8-diethyl-7,7-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-15 and B-23 to provide the title product; 42% yield. 1HNMR (300 MHz, Methanol-d4) δ 6.69 (d, J=10.6 Hz, 1H), 6.47 (d, J=8.9 Hz,1H), 5.82 (dd, J=8.2, 6.8 Hz, 2H), 4.16 (s, 2H), 3.37 (s, 2H), 2.63 (dq,J=27.4, 6.7 Hz, 4H), 0.44 (d, J=4.4 Hz, 6H), 0.02 (dt, J=13.6, 6.8 Hz,6H); ESMS (M+H)=474.24.

Compound 35:(7S)-5,7,8-triethyl-7-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-30 and B-23 to provide the title product; 62% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.56(s, 1H), 7.20 (dd, J=13.3, 5.9 Hz, 2H), 5.57 (s, 2H), 4.65 (d, J=2.6 Hz,2H), 4.02 (dt, J=14.3, 7.1 Hz, 1H), 3.96-3.77 (m, 2H), 3.56 (dq, J=13.4,6.6 Hz, 1H), 2.15-1.90 (m, 2H), 1.70 (s, 3H), 1.21 (t, J=7.0 Hz, 6H),0.76 (d, J=7.4 Hz, 3H); ESMS (M+H)=488.28.

Compound 235:(7R)-5,7,8-triethyl-7-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

This compound was made in a similar manner as described above usingintermediates A-28 and B-28. 1H NMR (300 MHz, Methanol-d4) δ 6.73 (s,1H), 6.58 (s, 1H), 5.86 (s, 1H), 5.78 (dd, J=8.5, 5.3 Hz, 2H), 5.45 (t,J=8.7 Hz, 2H), 3.93 (s, 2H), 2.96 (d, J=3.2 Hz, 2H), 2.41-2.24 (m, 1H),2.20-2.01 (m, 2H), 1.82 (dq, J=13.8, 6.9 Hz, 1H), 1.61 (dd, J=3.2, 1.6Hz, 1H), 1.04 (s, 1H), 0.61 (s, 2H), 0.47-0.16 (m, 2H); ESMS(M+1)=452.31.

Compound 39:(7S)-7-(2-Hydroxyethyl)-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-25 and B-23 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.79 (s, 1H), 7.59 (d, J=0.8 Hz, 1H), 7.19 (s, 1H),6.95 (dd, J=8.4, 6.6 Hz, 2H), 5.29 (s, 2H), 4.64-4.43 (m, 3H), 3.74 (dd,J=6.8, 5.5 Hz, 2H), 2.31-2.00 (m, 2H); ESMS (M+1)=434.14.

Compound 37:(7S)-5,8-diethyl-7-(2-hydroxyethyl)-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-26 and B-23 to provide the title product; 4% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.54 (d, J=14.2 Hz, 1.5H),7.42 (s, 0.5H), 7.03-6.91 (m, 2H), 5.29 (s, 2H), 4.67-4.39 (m, 4H),4.24-3.77 (m, 4H), 3.75-3.36 (m, 2H), 2.53-2.21 (m, 2H), 1.32-1.12 (m,6H; ESMS (M+H)=490.26.

Compound 233:5′,8′-diethyl-2′-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-37 and B-23 to provide the title product; 46% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.13 (s, 1H), 7.92 (s, 1H), 7.47 (d, J=3.3Hz, 1H), 7.14-7.06 (m, 2H), 5.47 (s, 2H), 4.58 (s, 2H), 3.85 (q, J=7.1Hz, 2H), 3.48-3.36 (77m, 2H), 1.65-1.52 (m, 2H), 1.53-1.42 (m, 2H),1.24-1.16 (m, 3H), 1.16-1.06 (m, 3H); ESMS (M+H)=472.21.

Compound 23:(7S)-5,8-dimethyl-7-propyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-50 and B-23 to provide the title product; 45% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.71-7.64 (m, 1H), 77.52 (d, J=3.1 Hz, 2H),6.92 (dd, J=8.5, 6.6 Hz, 2H), 5.30-5.23 (m, 2H), 4.40 (s, 2H), 4.19 (dd,J=5.8, 4.2 Hz, 1H), 3.26 (s, 3H), 3.06 (s, 3H), 1.90-1.70 (m, 2H),1.30-1.09 (m, 2H), 0.87 (t, J=7.3 Hz, 3H); ESMS (M+H)=460.19.

Compound 25:(7S)-5,8-dimethyl-7-(prop-2-yn-1-yl)-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-10 and B-23 to provide the title product; 5% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.81 (d, J=0.8 Hz, 1H), 7.63-7.56 (m, 1H),7.42 (s, 1H), 6.98 (dd, J=8.4, 6.6 Hz, 2H), 5.30 (d, J=1.1 Hz, 2H),4.62-4.49 (m, 3H), 3.29 (d, J=1.5 Hz, 6H), 3.06 (ddd, J=17.6, 4.8, 2.7Hz, 1H), 2.90 (dt, J=18.0, 2.9 Hz, 1H); ESMS (M+H)=456.19.

Compound 21:(7S)-7-((R)-1-methoxyethyl)-5,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-20 and B-23 to provide the title product; 6% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.78 (s, 1H), 7.59 (dd, J=1.9, 0.8 Hz, 1H),7.38 (d, J=13.5 Hz, 1H), 7.03-6.91 (m, 2H), 5.30 (s, 2H), 4.54 (s, 2H),4.39 (dd, J=11.5, 2.7 Hz, 1H), 3.93-3.75 (m, 1H), 3.35 (s, 3H),3.28-3.22 (m, 6H), 1.24 (dd, J=23.0, 6.5 Hz, 3H); ESMS (M+H)=476.17.

Compound 140:(7S)-2-(((1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-11 to provide the title product; 72% yield. 1HNMR (300 MHz, CDCl₃) δ 8.41 (s, 1H), 7.54 (s, 1H), 7.37 (s, 1H),7.21-6.88 (m, 3H), 5.22 (s, 2H), 4.85 (t, J=5.7 Hz, 1H), 4.43 (d, J=5.7Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.05 (s, 3H), 2.24 (s, 3H), 1.41 (d,J=6.8 Hz, 3H); ESMS (M+H)=414.12.

Compound 28:(7S)-2-(((1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-11 to provide the title product; 4% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.80 (s, 1H), 7.60 (s, 1H), 7.31-7.01 (m,3H), 5.31 (s, 2H), 4.54 (s, 2H), 4.31 (q, J=6.9 Hz, 1H), 3.32 (s, 3H),3.24 (s, 3H), 2.46 (s, 3H), 1.37 (d, J=7.0 Hz, 3H); ESMS (M+H)=428.23.

Compound 141:(7S)-2-(((1-(3,4-difluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-11 to provide the title product; 45% yield. 1HNMR (300 MHz, CDCl₃) δ 7.57 (s, 1H), 7.41 (d, J=19.3 Hz, 2H), 7.20-6.90(m, 4H), 5.22 (s, 2H), 4.46 (d, J=5.6 Hz, 2H), 4.06 (q, J=6.8 Hz, 1H),3.08 (s, 3H), 1.44 (d, J=6.8 Hz, 3H); ESMS (M+H)=400.12.

Compound 29:(7S)-2-(((1-(2,4-difluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-12 to provide the title product; 4% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.76 (s, 1H), 7.58 (s, 1H), 7.29 (td,J=8.5, 6.3 Hz, 1H), 7.07-6.89 (m, 3H), 5.35 (s, 2H), 4.52 (s, 2H),4.38-4.22 (m, 1H), 3.32 (s, 3H), 3.24 (s, 3H), 2.45 (s, 3H), 1.37 (d,J=7.0 Hz, 3H); ESMS (M+H)=428.23.

Compound 65:(7S)-2-(((1-(2-chloro-4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-13 to provide the title product; 6% yield. 1HNMR (300 MHz, CDCl₃) δ 7.55 (s, 1H), 7.43 (s, 1H), 7.16 (dd, J=8.3, 2.5Hz, 1H), 7.09-6.89 (m, 2H), 5.35 (s, 2H), 4.80 (t, J=5.8 Hz, 1H), 4.43(d, J=5.7 Hz, 2H), 4.09 (q, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.20 (s, 3H),1.41 (d, J=6.9 Hz, 3H); ESMS (M+H)=430.21.

Compound 66:(7S)-2-(((1-(4-fluoro-2-methylbenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-14 to provide the title product; 55% yield. 1HNMR (300 MHz, CDCl₃) δ 7.75 (s, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.22 (d,J=0.8 Hz, 1H), 7.09-6.82 (m, 3H), 5.24 (s, 2H), 4.78 (t, J=5.6 Hz, 1H),4.40 (d, J=5.6 Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.04 (s, 3H), 2.23 (d,J=16.9 Hz, 6H), 1.40 (d, J=6.9 Hz, 3H); ESMS (M+H)=410.23.

Compound 67:(7S)-2-(((1-(4-fluoro-2-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-15 to provide the title product; 76% yield. 1HNMR (300 MHz, CDCl₃) δ 7.57 (s, 1H), 7.45-7.35 (m, 2H), 7.18 (td, J=8.2,2.7 Hz, 1H), 7.02 (dd, J=8.5, 5.5 Hz, 1H), 5.45 (s, 2H), 4.44 (d, J=5.7Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.63 (s, 1H), 2.24 (s,3H), 1.41 (d, J=6.8 Hz, 3H); ESMS (M+H)=464.2.

Compound 17:(7S)-4,5,7,8-tetramethyl-2-(((1-(2,3,4-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-22 to provide the title product; 53% yield. 1HNMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.10 (s, 1H), 7.84 (s, 1H), 7.48(d, J=0.8 Hz, 1H), 7.32 (dddd, J=10.2, 9.3, 7.3, 2.1 Hz, 1H), 7.20-6.98(m, 1H), 5.44 (s, 2H), 5.39 (s, 2H), 4.42 (d, J=5.7 Hz, 2H), 4.36 (q,J=7.0 Hz, 1H), 3.22 (s, 3H), 3.17 (s, 3H), 2.42 (s, 3H), 1.27 (d, J=6.9Hz, 3H); ESMS (M+H)=446.3.

Compound 16:(7S)-4,5,7,8-tetramethyl-2-(((1-(2,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-24 to provide the title product; 53% yield 1HNMR (300 MHz, CDCl₃) δ 7.53 (s, 1H), 7.44 (s, 1H), 7.03-6.86 (m, 2H),5.25 (s, 2H), 5.21 (s, 1H), 4.44 (d, J=5.8 Hz, 2H), 4.01 (q, J=6.9 Hz,1H), 3.29 (s, 3H), 3.02 (s, 3H), 2.36 (s, 3H), 1.21 (d, J=6.9 Hz, 3H);ESMS (M+H)=446.3. Chiralpak IB column (25% ethanol/75% hexane): Rt10.838 mins.; 96.2% ee. [α]_(D) ²⁰+15.2° (c=1, methanol).

Compound 18:(7S)-4,5,7,8-tetramethyl-2-(((1-(2,4,6-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-80 to provide the title product; 35% yield 1HNMR (300 MHz, Methanol-d4) δ 7.72 (s, 1H), 7.50 (d, J=0.7 Hz, 1H), 6.95(ddd, J=9.0, 7.8, 4.7 Hz, 2H), 5.36 (d, J=1.2 Hz, 2H), 4.50 (d, J=1.8Hz, 2H), 4.38-4.19 (m, 1H), 3.25 (s, 3H), 2.45 (s, 3H), 1.99 (s, 3H),1.37 (d, J=7.0 Hz, 3H); ESMS (M+H)=446.15.

Compound 146:(7S)-2-(((1-(3-fluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-17 to provide the title product; 52% yield 1HNMR (300 MHz, CDCl₃) δ 8.02 (s, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.38-7.31(m, 1H), 7.02-6.87 (m, 3H), 5.19 (s, 2H), 4.91 (s, 1H), 4.42 (d, J=5.7Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.89 (s, 3H), 3.05 (s, 3H), 2.23 (s,3H), 1.41 (d, J=6.9 Hz, 3H); ESMS (M+H)=426.32

Compound 75:(7S)-2-(((1-(4-fluoro-3-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-16 to provide the title product; 84% yield 1HNMR (400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.45 (d, J=0.8 Hz, 1H), 7.27 (d,J=0.8 Hz, 1H), 6.96 (ddd, J=11.0, 8.2, 0.8 Hz, 1H), 6.75 (dd, J=8.0, 2.1Hz, 1H), 6.67 (ddd, J=8.4, 4.2, 2.1 Hz, 1H), 5.13 (s, 2H), 4.79 (s, 1H),4.34 (dd, J=5.5, 1.3 Hz, 2H), 4.06-3.94 (m, 1H), 3.77 (d, J=0.8 Hz, 3H),2.96 (d, J=0.9 Hz, 3H), 2.14 (s, 3H), 1.32 (dd, J=6.8, 0.9 Hz, 3H); ESMS(M+H)=426.18.

Compound 148:(7S)-2-(((1-(3-fluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-17 to provide the title product; 34% yield 1HNMR (300 MHz, CDCl₃) δ 7.54 (d, J=0.8 Hz, 1H), 7.45-7.37 (m, 2H),7.03-6.86 (m, 3H), 5.19 (s, 2H), 4.44 (d, J=5.7 Hz, 2H), 4.09 (q, J=6.8Hz, 1H), 3.88 (s, 3H), 3.08 (s, 3H), 1.46 (d, J=6.9 Hz, 3H); ESMS(M+H)=411.98.

Compound 181:(7S)-2-(((1-(benzo[d][1,3]dioxol-5-ylmethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-19 to provide the title product; 31% yield. 1HNMR (300 MHz, CDCl₃) δ 7.50 (d, J=0.8 Hz, 1H), 7.39 (d, J=0.8 Hz, 1H),6.84-6.67 (m, 3H), 5.96 (s, 2H), 5.16 (s, 2H), 4.44 (d, J=5.7 Hz, 2H),4.15 (q, J=6.8 Hz, 1H), 3.14 (s, 3H), 2.32 (s, 3H), 1.50 (d, J=6.9 Hz,3H); ESMS (M+H)=422.18.

Compound 83:(7S)-2-(((1-(4-fluoro-2-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-1 to provide the title product; 84% yield. 1HNMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H),6.98-6.92 (m, 1H), 6.93-6.87 (m, 1H), 6.70 (td, J=8.5, 2.5 Hz, 1H), 6.52(t, J=6.0 Hz, 1H), 5.15 (s, 2H), 4.18 (dd, J=8.4, 6.5 Hz, 1H), 3.99 (q,J=6.7 Hz, 1H), 3.80 (s, 3H), 3.08 (s, 1H), 2.93 (s, 3H), 2.12 (s, 3H),1.18 (d, J=6.8 Hz, 3H); ESMS (M+H)=426.3.

Compound 84:(7S)-2-(((1-(4-fluoro-2-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-1 to provide the title product; 30% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.36 (s, 2H), 7.48 (dt, J=22.5, 11.3 Hz,1H), 6.88 (ddd, J=9.7, 7.4, 2.4 Hz, 1H), 6.80-6.69 (m, 1H), 5.59 (s,2H), 4.62 (d, J=15.7 Hz, 2H), 4.32 (q, J=6.9 Hz, 1H), 3.86 (s, 3H),3.35-3.31 (m, 4H), 3.21 (s, 3H), 2.51 (s, 3H), 1.37 (d, J=7.0 Hz, 3H);ESMS (M+H)=440.26.

Compound 87:(7S)-2-(((1-(4-fluoro-2-hydroxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-(((1-(4-Fluoro-2-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(Compound 83; 350 mg, 0.765 mmol) was dissolved in 20 ml ofdichloromethane. A 1M solution of boron tribromide (4.6 ml, 4.6 mmol)was added to the solution and stirred at room temperature for 18 hours.The reaction was quenched by the addition of methanol followed byevaporation of the reaction mixture in vacuo. The resulting crudeproduct was purified by preparative HPLC (C18 column; 10-100%Acetonitrile/water (0.1% TFA)). The desired fractions were evaporated invacuo to afford the title product. wt. 249 mg (71% yield). 1H NMR (300MHz, Methanol-d4) δ 8.35 (d, J=3.7 Hz, 2H), 7.46 (dd, J=8.4, 6.6 Hz,1H), 6.76-6.56 (m, 2H), 4.62 (s, 2H), 4.33 (q, J=6.9 Hz, 1H), 3.19 (s,3H), 2.34 (s, 3H), 1.52 (d, J=6.9 Hz, 3H); ESMS (M+H)=412.21.

Compound 44:(7S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-20 to provide the title product; 27% yield 1HNMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H), 7.49(s, 1H), 7.27 (s, 1H), 6.98 (d, J=8.9 Hz, 2H), 5.25 (s, 2H), 4.39 (d,J=5.6 Hz, 2H), 4.31 (q, J=6.9 Hz, 1H), 3.89 (d, J=1.0 Hz, 3H), 3.15 (s,3H), 1.44 (d, J=6.9 Hz, 3H); ESMS (M+H)=430.24.

Compound 48:(7S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,8-diethyl-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-26 and B-20 to provide the title product; 18% yield. 1HNMR (300 MHz, CDCl₃) δ 7.53 (d, J=0.8 Hz, 1H), 7.49-7.42 (m, 1H), 7.37(s, 1H), 6.75 (dq, J=8.2, 0.6 Hz, 2H), 5.18 (s, 2H), 4.52-4.32 (m, 3H),4.27-3.95 (m, 4H), 3.87-3.61 (m, 2H), 3.18 (ddt, J=14.1, 11.3, 7.1 Hz,1H), 2.30-2.10 (m, 1H), 1.88 (ddt, J=14.2, 9.5, 4.7 Hz, 1H), 1.34-1.18(m, 8H); ESMS (M+H)=502.3.

Compound 88:(7S)-2-(((1-(2,4-difluoro-3-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-21 to provide the title product; 75% yield. 1HNMR (300 MHz, CDCl₃) δ 9.33 (bs, 1H), 7.50 (d, J=1.4 Hz, 1H), 7.41 (s,1H), 6.92-6.70 (m, 2H), 5.25 (s, 2H), 4.97 (d, J=7.1 Hz, 1H), 4.47-4.34(m, 2H), 4.12-4.00 (m, 1H), 3.99 (q, J=1.2 Hz, 3H), 3.10-2.95 (m, 3H),2.25 (s, 3H), 1.46-1.30 (m, 3H); ESMS (M+H)=444.28.

Compound 63:(7S)-5-fluoro-2-((4-(((4,5,7,8-tetramethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzonitrile

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-18 to provide the title product; 27% yield. 1HNMR (300 MHz, CDCl₃) δ 7.55 (d, J=4.0 Hz, 2H), 7.44-7.26 (m, 3H), 5.45(d, J=1.7 Hz, 2H), 4.88 (t, J=5.9 Hz, 1H), 4.45 (dd, J=5.8, 1.7 Hz, 2H),4.08-3.94 (m, 1H), 3.31 (d, J=1.5 Hz, 3H), 3.02 (d, J=1.5 Hz, 3H), 2.36(d, J=1.5 Hz, 3H), 1.21 (dd, J=6.9, 1.6 Hz, 3H); ESMS (M+H)=435.37.

Compound 64:(7S)-5-fluoro-2-((4-(((4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)benzonitrile

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-18 to provide the title product; 27% yield. 1HNMR (300 MHz, CDCl₃) δ 7.59-7.50 (m, 3H), 7.39 (dt, J=7.7, 1.6 Hz, 1H),7.34-7.24 (m, 2H), 5.44 (d, J=0.8 Hz, 2H), 4.83 (t, J=5.8 Hz, 1H), 4.44(d, J=5.8 Hz, 2H), 4.09 (q, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.21 (s, 3H),1.41 (d, J=6.9 Hz, 3H); ESMS (M+H)=421.3.

Compound 8:(7S)-2-(((1-(4-fluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-25 to provide the title product; 13% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.53 (s, 1H), 7.34 (s, 1H), 7.07-6.96 (m,2H), 6.95-6.82 (m, 2H), 4.43 (d, J=2.4 Hz, 2H), 4.32 (tdd, J=6.9, 4.4,3.1 Hz, 3H), 3.34 (s, 3H), 3.21 (s, 3H), 3.08 (t, J=6.8 Hz, 2H), 2.46(s, 3H), 1.38 (d, J=7.0 Hz, 3H); ESMS (M+H)=424.3.

Compound 6:(7S)-2-(((1-(4-fluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-25 to provide the title product; 13% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.52 (s, 1H), 7.36-7.29 (m, 1H), 7.06-6.95(m, 2H), 6.94-6.81 (m, 2H), 4.41 (d, J=2.0 Hz, 2H), 4.39-4.24 (m, 3H),3.24 (d, J=19.9 Hz, 3H), 3.08 (t, J=6.7 Hz, 2H), 2.30 (d, J=2.7 Hz, 3H),1.55 (dd, J=8.1, 7.0 Hz, 3H); ESMS (M+H)=410.3.

Compound 13:(7S)-2-(((1-(4-fluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-7-(2-hydroxyethyl)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-25 and B-25 to provide the title product. ESMS(M+1)=412.24.

Compound 123:(7S)-4,7,8-trimethyl-2-(((1-(3,4,5-trifluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-28 to provide the title product; 6% yield. 1HNMR (300 MHz, CDCl₃) δ 7.89 (s, 1H), 7.44 (d, J=0.8 Hz, 1H), 7.06 (d,J=0.8 Hz, 1H), 6.55 (dd, J=8.3, 6.5 Hz, 2H), 4.70 (t, J=5.8 Hz, 1H),4.30 (dd, J=5.8, 2.7 Hz, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.00 (q, J=6.8 Hz,1H), 2.99 (d, J=16.7 Hz, 5H), 2.14 (s, 3H), 1.33 (d, J=6.8 Hz, 3H); ESMS(M+H)=446.2.

Compound 103:(7S)-2-(((1-(2-(4-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-33 to provide the title product; 57% yield. 1HNMR (300 MHz, CDCl₃): ppm 2.05-2.16 (m, 1H), 2.19 (s, 3H), 2.26-2.38 (m,1H), 2.77 (d, J=6.7 Hz, 2H), 3.04-3.22 (m, 1H), 3.29-3.80 (m, 4H), 4.43(d, J=5.7 Hz, 2H), 4.81-5.03 (m, 1H), 5.21 (s, 2H), 5.57 (s, 1H),6.97-7.06 (m, 2H), 7.13-7.20 (m, 2H), 7.34 (s, 1H), 7.51 (s, 1H); ESMS(M+H)=396.2.

Compound 109:(7S)-2-(((1-(2-(4-fluorophenoxy)ethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-33 to provide the title product; 34% yield. 1HNMR (300 MHz, CDCl₃) δ 7.58-7.50 (m, 2H), 7.41 (s, 1H), 7.01-6.88 (m,2H), 6.83-6.72 (m, 2H), 4.45 (ddd, J=5.8, 4.6, 1.4 Hz, 4H), 4.29 (dd,J=5.6, 4.9 Hz, 2H), 4.07 (q, J=6.8 Hz, 1H), 3.08 (s, 3H), 1.45 (d, J=6.9Hz, 3H); ESMS (M+H)=412.26.

Compound 104:(7S)-2-(((1-(3-(4-fluorophenyl)propyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-32 to provide the title product; 50% yield. 1HNMR (300 MHz, CDCl₃) δ 7.51 (d, J=0.8 Hz, 1H), 7.34 (d, J=0.8 Hz, 1H),7.18-7.07 (m, 2H), 7.05-6.92 (m, 2H), 4.88-4.79 (m, 1H), 4.48-4.39 (m,2H), 4.08 (td, J=7.0, 2.4 Hz, 3H), 3.07 (s, 3H), 2.58 (dd, J=8.5, 6.7Hz, 2H), 2.27-2.09 (m, 5H), 1.41 (d, J=6.8 Hz, 3H); ESMS (M+H)=424.2.

Compound 110:(7S)-2-(((1-(3-(4-fluorophenyl)propyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-32 to provide the title product; 49% yield. 1HNMR (300 MHz, CDCl₃) δ 7.53 (d, J=0.8 Hz, 1H), 7.44-7.35 (m, 2H),7.18-7.07 (m, 2H), 7.03-6.91 (m, 2H), 4.46 (dd, J=5.7, 2.7 Hz, 2H), 4.07(td, J=6.9, 4.5 Hz, 3H), 3.09 (s, 3H), 2.58 (dd, J=8.5, 6.7 Hz, 2H),2.25-2.08 (m, 2H), 1.44 (d, J=6.9 Hz, 3H); ESMS (M+H)=410.27.

Compound 105:(7S)-2-(((1-(3,4-difluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-26 to provide the title product; 52% yield. 1HNMR (300 MHz, CDCl₃) δ 7.77 (s, 1H), 7.53 (d, J=0.8 Hz, 1H), 7.17-6.95(m, 2H), 6.90-6.67 (m, 2H), 4.81 (t, J=5.7 Hz, 1H), 4.38 (dd, J=5.8, 2.4Hz, 2H), 4.27 (t, J=7.0 Hz, 2H), 4.16-4.02 (m, 1H), 3.09 (d, J=18.5 Hz,5H), 2.22 (s, 3H), 1.42 (d, J=6.9 Hz, 3H); ESMS (M+H)=428.24.

Compound 111:(7S)-2-(((1-(3,4-difluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-26 to provide the title product; 55% yield. 1HNMR (300 MHz, CDCl₃) δ 7.54 (d, J=0.7 Hz, 1H), 7.43 (s, 1H), 7.17 (s,1H), 7.02 (dt, J=10.3, 8.3 Hz, 1H), 6.90-6.72 (m, 2H), 4.40 (dd, J=5.8,3.5 Hz, 2H), 4.27 (t, J=7.0 Hz, 2H), 4.11 (q, J=6.8 Hz, 1H), 3.10 (d,J=11.6 Hz, 4H), 1.46 (d, J=6.9 Hz, 3H); ESMS (M+H)=414.24.

Compound 119:(7S)-2-(((1-(2,4-difluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-27 to provide the title product; 26% yield. 1HNMR (300 MHz, CDCl₃) δ 7.53 (s, 1H), 7.42 (s, 1H), 7.21 (s, 1H),6.96-6.64 (m, 3H), 4.40 (dd, J=5.9, 3.4 Hz, 2H), 4.27 (t, J=7.1 Hz, 2H),4.10 (q, J=6.9 Hz, 1H), 3.12 (d, J=18.1 Hz, 5H), 1.47 (d, J=6.8 Hz, 3H);ESMS (M+H)=414.19.

Compound 106:(7S)-2-(((1-(2,4-difluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-27 to provide the title product; 38% yield. 1HNMR (300 MHz, CDCl₃) δ 7.51 (d, J=0.8 Hz, 2H), 7.16 (d, J=0.8 Hz, 1H),6.96-6.65 (m, 4H), 4.75 (t, J=5.8 Hz, 1H), 4.42-4.23 (m, 4H), 4.16-4.03(m, 2H), 3.21-3.10 (m, 2H), 3.06 (s, 3H), 2.21 (s, 3H), 1.42 (d, J=6.9Hz, 3H); ESMS (M+H)=428.24.

Compound 121:(7S)-2-(((1-(4-ethoxyphenethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-31 to provide the title product; 37% yield. 1HNMR (300 MHz, CDCl₃) δ 7.54 (d, J=0.8 Hz, 1H), 7.41 (s, 1H), 7.22 (d,J=0.8 Hz, 1H), 6.99 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 4.41 (dd,J=5.7, 1.8 Hz, 2H), 4.31-4.19 (m, 2H), 4.05 (dq, J=27.2, 6.9 Hz, 3H),3.09 (s, 5H), 1.51-1.35 (m, 6H); ESMS (M+H)=422.25.

Comp 108:(7S)-2-(((1-(4-ethoxyphenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-31 to provide the title product; 55% yield. 1HNMR (300 MHz, CDCl₃) δ 7.76 (s, 1H), 7.52 (s, 1H), 7.16 (s, 1H),7.03-6.93 (m, 2H), 6.85-6.76 (m, 2H), 4.79 (t, J=5.6 Hz, 1H), 4.38 (d,J=5.6 Hz, 2H), 4.26 (t, J=7.3 Hz, 2H), 4.05 (dq, J=21.0, 6.9 Hz, 3H),3.07 (d, J=6.5 Hz, 5H), 2.23 (s, 3H), 1.48-1.36 (m, 6H); ESMS(M+H)=436.29.

Compound 120:(7S)-2-(((1-(3,5-difluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-1 and B-30 to provide the title product; 8% yield. 1HNMR (300 MHz, CDCl₃) δ 7.54 (d, J=0.8 Hz, 1H), 7.42 (s, 1H), 7.25-7.18(m, 1H), 6.72-6.53 (m, 3H), 4.46-4.36 (m, 2H), 4.29 (t, J=7.1 Hz, 2H),4.10 (q, J=6.8 Hz, 1H), 3.20-3.05 (m, 5H), 1.46 (d, J=6.8 Hz, 3H); ESMS(M+H)=414.19.

Compound 107:(7S)-2-(((1-(3,5-difluorophenethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-30 to provide the title product; 6.4% yield. 1HNMR (300 MHz, CDCl₃) δ 7.53 (d, J=0.7 Hz, 1H), 7.41 (s, 1H), 7.17 (d,J=0.8 Hz, 1H), 6.74-6.53 (m, 3H), 4.81 (s, 1H), 4.44-4.23 (m, 4H), 4.10(q, J=6.9 Hz, 1H), 3.15 (t, J=7.1 Hz, 2H), 3.06 (s, 3H), 2.21 (s, 3H),1.42 (d, J=6.8 Hz, 3H); ESMS (M+H)=428.24.

Compound 112:(7S)-2-(((trans-1-(3-(4-fluorophenyl)cyclobutyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-34 to provide the title product; 80% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.71 (s, 1H), 7.53 (s, 1H), 7.40-7.29 (m,2H), 7.11-6.99 (m, 2H), 5.01-4.89 (m, 1H), 4.40 (s, 2H), 4.08 (q, J=6.8Hz, 1H), 3.81-3.63 (m, 1H), 3.08 (s, 3H), 2.93 (ddd, J=13.0, 6.5, 3.0Hz, 2H), 2.71-2.56 (m, 2H), 2.18 (s, 3H), 1.33 (d, J=6.8 Hz, 4H); ESMS(M+H)=436.25.

Compound 137:(7S)-2-(((1-(3-(4-fluorophenyl)cyclopentyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-51 to provide the title product, 82% yield. ESMS(M+1)=450.17.

Compound 113:(7S)-2-(((1-(2-cyclohexylethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-35 to provide the title product; 94% yield. 1HNMR (300 MHz, CDCl₃) δ 7.84 (s, OH), 7.48 (d, J=0.8 Hz, 1H), 7.35 (d,J=0.8 Hz, 1H), 4.83 (s, 1H), 4.47-4.36 (m, 2H), 4.17-4.04 (m, 3H), 3.07(s, 3H), 2.24 (d, J=1.0 Hz, 3H), 1.79-1.59 (m, 7H), 1.42 (d, J=6.9 Hz,3H), 1.23 (ddd, J=22.4, 7.7, 3.9 Hz, 3H), 1.06-0.82 (m, 3H); ESMS(M+H)=398.26.

Compound 115:(7S)-4,7,8-trimethyl-2-(((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-36 to provide the title product; 21% yield. 1HNMR (300 MHz, CDCl₃) δ 8.61 (s, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 4.89(d, J=6.4 Hz, 1H), 4.35 (d, J=5.6 Hz, 2H), 4.03 (dt, J=8.8, 7.0 Hz, 3H),3.93-3.72 (m, 2H), 3.28 (td, J=11.6, 2.0 Hz, 2H), 2.99 (s, 3H), 2.18 (s,3H), 1.73 (q, J=7.0 Hz, 2H), 1.60-1.47 (m, 2H), 1.33 Compound 58 (d,J=6.9 Hz, 3H), 1.20 (t, J=5.3 Hz, 3H); ESMS (M+H)=400.15.

Compound 58:(7S)-2-(((1-((4,4-difluorocyclohexyl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-37 to provide the title product; 15% yield. 1HNMR (400 MHz, CDCl₃) δ 7.39 (d, J=4.7 Hz, 2H), 4.41 (dd, J=12.9, 6.5 Hz,2H), 4.08 (q, J=6.4 Hz, 1H), 3.39 (d, J=4.0 Hz, 2H), 3.08 (d, J=4.4 Hz,3H), 2.22 (d, J=4.4 Hz, 3H), 2.16-2.04 (m, 3H), 1.98 (t, J=9.4 Hz, 1H),1.84-1.57 (m, 4H), 1.48-1.36 (m, 3H); ESMS (M+H)=420.33.

Compound 5:(7S)-2-(((1-(cyclobutylmethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-38 to provide the title product; 29% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.69 (s, 1H), 7.56 (s, 1H), 4.51 (s, 2H),4.31 (q, J=6.9 Hz, 1H), 4.14 (d, J=7.3 Hz, 2H), 3.26 (s, 3H), 2.79 (p,J=7.6 Hz, 1H), 2.29 (s, 3H), 2.11-1.72 (m, 6H), 1.58-1.49 (m, 3H); ESMS(M+H)=356.3.

Compound 7:(7S)-2-(((1-(cyclobutylmethyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-38 to provide the title product; 25% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.51 (s, 1H), 4.52 (s, 2H),4.32 (q, J=7.0 Hz, 1H), 4.12 (d, J=7.3 Hz, 2H), 3.33 (s, 3H), 3.27 (s,3H), 2.86-2.70 (m, 1H), 2.46 (s, 3H), 2.11-1.71 (m, 6H), 1.38 (d, J=7.0Hz, 3H); ESMS (M+H)=370.34.

Compound 61:(7S)-2-(((1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method AB via reaction ofintermediates A-2 and B-39 to provide the title product; 13% yield. 1HNMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.60 (s, 1H), 7.36 (s, 1H), 6.50(t, J=6.0 Hz, 1H), 4.21 (dd, J=6.0, 2.1 Hz, 2H), 4.15 (d, J=6.3 Hz, 2H),4.00 (q, J=6.8 Hz, 1H), 2.95 (s, 3H), 2.58 (dddd, J=17.9, 9.3, 4.8, 1.8Hz, 2H), 2.46-2.26 (m, 2H), 2.13 (s, 3H), 1.19 (d, J=6.8 Hz, 3H); ESMS(M+H)=392.25.

Compound 133:(7S)-2-(((1-(2-cyclopentylethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-40 to provide the title product; 42% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.55 (s, 1H), 7.43 (s, 1H), 4.37 (s, 2H),4.13-4.02 (m, 3H), 3.07 (s, 3H), 2.18 (s, 3H), 1.88-1.43 (m, 9H), 1.33(d, J=6.8 Hz, 3H), 1.20-1.02 (m, 2H); ESMS (M+H)=384.25.

Compound 134:(7S)-2-(((1-(bicyclo[2.2.1]heptan-2-ylmethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-43 to provide the title product as a mixture ofdiastereomers; 22% yield. 1H NMR (300 MHz, Methanol-d4) δ 7.56 (s, 1H),7.42 (s, 1H), 4.38 (s, 2H), 4.18-4.02 (m, 2H), 3.86 (qd, J=13.7, 7.9 Hz,1H), 3.09 (s, 3H), 2.47-2.31 (m, 1H), 2.19 (s, 4H), 1.95 (d, J=16.3 Hz,1H), 1.80-1.46 (m, 3H), 1.36 (t, J=8.4 Hz, 6H), 1.20 (ddd, J=23.4, 14.1,4.7 Hz, 2H), 0.78 (ddd, J=12.3, 5.4, 2.1 Hz, 1H); ESMS (M+H)=396.27.

The diastereomers were initially separated by SFC (column: ChiralpakAD-H, 10×250 mm [30% MeOH (0.2% diethylamine)/70% CO₂, isocratic; 10ml/min). to afford peak C and D and a mixture of peaks A and B.Stereochemistry was arbitrarily assigned.

Compound 150

Peak C: Retention time: 1.193 min (99% de); wt. 17 mg ¹H NMR (300 MHz,Methanol-d4) δ 7.55 (s, 1H), 7.42 (s, 1H), 4.37 (s, 2H), 4.07 (dd,J=7.5, 4.7 Hz, 3H), 3.07 (s, 3H), 2.48-2.29 (m, 1H), 2.18 (s, 4H), 1.97(s, 1H), 1.80-1.47 (m, 3H), 1.46-1.15 (m, 8H), 0.78 (ddd, J=12.3, 5.4,2.2 Hz, 1H). ESMS (M+1)=396.21

Compound 151

Peak D: Retention time: 1.375 min (99.2% de) 23 mg ¹H NMR (300 MHz,Methanol-d4) δ 7.55 (s, 1H), 7.41 (s, 1H), 4.37 (s, 2H), 4.07 (dd,J=7.5, 3.0 Hz, 3H), 3.07 (s, 3H), 2.47-2.29 (m, 1H), 2.19 (d, J=6.3 Hz,4H), 1.97 (s, 1H), 1.63 (dtdd, J=23.1, 15.7, 7.7, 3.5 Hz, 3H), 1.44-1.09(m, 8H), 0.78 (ddd, J=12.3, 5.5, 2.1 Hz, 1H). ESMS (M+1)=396.32

Compounds 156 and 157

(Peaks A & B) were separated by chiral HPLC (column: Chiralpak OJ-H; 20%1:1 MeOH:EtOH/80% Hexanes (0.2% DEA), isocratic, 20 ml/min).

Compound 156

Peak A: Retention time: 11.38 minutes (100% de) 9.3 mg; ESMS(M+1)=396.36.

Compound 157

Peak B: Retention time: 13.89 min (96.4% de) 8.0 mg ESMS (M+1)=396.32Compound 114:(7S)-4,7,8-trimethyl-2-(((1-((S)-2-methylbutyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-42 to provide the title product; 18% yield. 1HNMR (300 MHz, CDCl₃) δ 7.96 (s, 1H), 7.49 (d, J=0.7 Hz, 1H), 7.33 (d,J=0.8 Hz, 1H), 4.85 (s, 1H), 4.43 (d, J=5.6 Hz, 2H), 4.09 (q, J=6.9 Hz,1H), 4.00 (dd, J=13.6, 6.6 Hz, 1H), 3.83 (dd, J=13.6, 7.8 Hz, 1H), 3.07(s, 3H), 2.24 (s, 3H), 2.07-1.87 (m, 1H), 1.42 (d, J=6.9 Hz, 3H),1.41-1.03 (m, 2H), 0.99-0.88 (m, 3H), 0.86 (d, J=6.7 Hz, 3H); ESMS(M+H)=358.23.

Compound 118:(7S)-4,7,8-trimethyl-2-(((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-65 to provide the title product; 56% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.64 (s, 1H), 7.46 (s, 1H), 4.45-4.25 (m,3H), 4.14-3.93 (m, 3H), 3.62-3.44 (m, 2H), 3.07 (s, 3H), 2.18 (s, 3H),2.02 (ddd, J=12.2, 10.6, 3.9 Hz, 4H), 1.33 (d, J=6.8 Hz, 3H); ESMS(M+H)=372.23.

Compound 126:(7S)-4,7,8-trimethyl-2-(((6-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-149 to provide the title product; 8% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.07 (d, J=5.9 Hz, 2H), 7.95 (s, 1H),7.62-7.45 (m, 2H), 6.63 (d, J=8.5 Hz, 2H), 6.33 (s, 1H), 5.49 (s, 1H),4.57 (s, 1H), 4.39 (s, 2H), 4.06 (d, J=6.8 Hz, 1H), 3.88 (d, J=1.0 Hz,2H), 3.57 (s, 1H), 3.05 (d, J=7.6 Hz, 3H), 2.17 (s, 3H), 1.32 (d, J=6.8Hz, 3H); ESMS (M+H)=462.24.

Compound 91:(7S)-2-(((1-(2-(4-fluorophenyl)-2-oxoethyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-45 to provide the title product; 18% yield. 1HNMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.09 (dd, J=8.9, 5.5 Hz, 2H),7.58 (d, J=0.8 Hz, 1H), 7.49-7.33 (m, 3H), 6.65 (d, J=6.4 Hz, 1H), 5.75(s, 2H), 4.25 (dd, J=6.1, 3.4 Hz, 2H), 4.00 (q, J=6.8 Hz, 1H), 3.33 (s,2H), 2.14 (s, 3H), 1.19 (d, J=6.8 Hz, 3H); ESMS (M+H)=424.24. ChiralHPLC 95.5% ee.

Compound 116:(7S)-2-(((1-(2,3-dihydro-1H-inden-2-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-44 to provide the title product; 53% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.19 (d, J=9.9 Hz, 1H), 7.29(t, J=8.9 Hz, 2H), 7.23 (dd, J=6.3, 2.3 Hz, 2H), 5.52 (dd, J=9.6, 5.4Hz, 1H), 4.56 (s, 2H), 4.34-4.24 (m, 1H), 3.65 (dd, J=16.7, 7.3 Hz, 2H),3.46-3.34 (m, 2H), 3.13 (d, J=0.8 Hz, 3H), 2.30 (dd, J=7.9, 3.7 Hz, 3H),1.51 (d, J=6.2 Hz, 3H); ESMS (M+1)=404.2.

Compound 117:(7S)-2-(((1-(6-fluoro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-46 to provide the title product; 61% yield. 1HNMR (400 MHz, Methanol-d4) δ 7.61 (dd, J=12.0, 6.1 Hz, 1H), 7.61-7.52(m, 1H), 7.37-7.21 (m, 1H), 7.03-6.89 (m, 1H), 6.77-6.61 (m, 1H), 5.84(d, J=5.2 Hz, 1H), 4.49 (s, 2H), 4.25 (dt, J=15.2, 7.4 Hz, 1H),3.37-3.26 (m, 1H), 3.24-3.15 (m, 3H), 3.17-3.01 (m, 1H), 2.92 (dd,J=14.0, 6.3 Hz, 1H), 2.67 (ddd, J=16.7, 10.5, 5.9 Hz, 1H), 2.39 (dt,J=21.8, 7.9 Hz, 1H), 2.31-2.25 (m, 3H), 1.55-1.45 (m, 3H); ESMS(M+1)=422.2.

Compound 97:(7S)-4,7,8-trimethyl-2-(((1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-47 to provide the title product; 61% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.27 (s, 1H), 8.13-7.91 (m, 2H), 7.82-7.50(m, 3H), 4.49 (s, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.09 (s, 3H), 2.23 (d,J=19.0 Hz, 3H), 1.34 (d, J=6.8 Hz, 3H); ESMS (M+1)=432.17. 95% ee.

Compound 98:(7S)-2-(((1-(2,4-difluorophenyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-48 to provide the title product; 61% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.97 (d, J=2.7 Hz, 1H), 7.84-7.61 (m, 2H),7.33-6.90 (m, 2H), 4.47 (s, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.09 (s, 3H),2.19 (s, 3H), 1.33 (d, J=6.8 Hz, 3H); ESMS (M+1)=400.32. 95% ee.

Compound 76:(7S)-2-(((1-(3,4-dimethoxybenzyl)-1H-pyrazol-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-49 to provide the title product; 20% yield. 1HNMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 6.77 (d,J=8.2 Hz, 1H), 6.73-6.63 (m, 2H), 6.22 (d, J=1.8 Hz, 1H), 5.34 (s, 2H),5.01-4.86 (m, 1H), 4.55 (dd, J=5.9, 2.4 Hz, 2H), 4.04 (q, J=6.8 Hz, 1H),3.84 (d, J=2.1 Hz, 3H), 3.77 (s, 3H), 2.95 (s, 3H), 2.24 (s, 3H), 1.37(d, J=6.8 Hz, 3H); ESMS (M+1)=438.25.

Compound 154 and compound 155:(7S)-2-(((1-((1R,2R)-2-(4-fluorophenyl)cyclopropyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand(7S)-2-(((1-((1S,2S)-2-(4-fluorophenyl)cyclopropyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof intermediate A-2 and(1-((cis)-2-(4-fluorophenyl)cyclopropyl)-1H-pyrazol-4-yl)methanamine toprovide the title products as a diastereomeric mixture (Compound 144).The diastereomers were separated by SFC (Column: AD-H column, 20×250 mm;35% IPA (0.2% diethylamine), 65% CO₂, isocratic) to provide diastereomerA & B:

Diastereomer A: Retention time: 1.023 mins.; 97.4% ee; 121 mg; 1H NMR(400 MHz, CDCl₃) δ 9.07 (s, 1H), 7.39 (d, J=4.3 Hz, 2H), 7.09-6.98 (m,2H), 6.91 (t, J=8.6 Hz, 2H), 4.89 (t, J=5.1 Hz, 1H), 4.40-4.27 (m, 2H),3.97 (q, J=6.7 Hz, 1H), 3.58 (dt, J=7.6, 3.9 Hz, 1H), 2.96 (s, 3H), 2.48(ddd, J=9.7, 6.6, 3.2 Hz, 1H), 2.18 (s, 3H), 1.77-1.64 (m, 1H), 1.31 (d,J=6.8 Hz, 3H); ESMS (M+1)=422.29.

Diastereomer B: Retention time: 1.214 mins.; 96.2% ee; 126 mg; 1H NMR(400 MHz, CDCl₃) δ 9.41 (s, 1H), 7.39 (s, 2H), 7.03 (dd, J=8.0, 5.5 Hz,2H), 6.89 (t, J=8.5 Hz, 2H), 5.16 (s, 1H), 4.39-4.25 (m, 2H), 3.97 (q,J=6.7 Hz, 1H), 3.56 (dt, J=7.6, 3.6 Hz, 1H), 2.97 (s, 3H), 2.47 (ddd,J=9.7, 6.6, 3.3 Hz, 1H), 2.19 (s, 3H), 1.70 (dt, J=10.0, 5.2 Hz, 1H),1.31 (d, J=6.7 Hz, 3H); ESMS (M+1)=422.29.

Compound 152 and compound 153:(7S)-2-(((1-((1R,2R)-2-(4-fluorophenyl)cyclopropyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-oneand(7S)-2-(((1-((1S,2S)-2-(4-fluorophenyl)cyclopropyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediate A-3 and(1-((cis)-2-(4-fluorophenyl)cyclopropyl)-1H-pyrazol-4-yl)methanamine toprovide the title products as a diastereomeric mixture (Compound 145).The diastereomers were separated by SFC (column: AD-H column, 10×250 mm;40% MeOH (0.2% diethylamine), 60% CO₂, isocratic) to providediastereomer A & B:

Diastereomer A: Retention time: 0.919 mins.; 99% ee; 51 mg; 1H NMR (400MHz, CDCl₃) δ 7.41 (s, 2H), 7.06 (dd, J=10.3, 3.4 Hz, 2H), 6.92 (dd,J=12.2, 5.0 Hz, 2H), 4.89 (s, 1H), 4.33 (dd, J=14.9, 5.9 Hz, 2H), 3.92(q, J=6.8 Hz, 1H), 3.58 (dt, J=7.6, 3.8 Hz, 1H), 3.22 (s, 3H), 2.94 (s,3H), 2.56-2.45 (m, 1H), 2.28 (s, 3H), 1.72 (dt, J=10.1, 5.2 Hz, 1H),1.39-1.29 (m, 1H), 1.12 (d, J=6.9 Hz, 3H); ESMS (M+1)=436.29.

Diastereomer B: Retention time: 11.118 mins.; 99% ee; 52 mg; 1H NMR (400MHz, CDCl₃) δ 7.41 (s, 2H), 7.10-6.97 (m, 2H), 6.92 (t, J=8.6 Hz, 2H),4.88 (s, 1H), 4.42-4.29 (m, 2H), 3.92 (q, J=6.8 Hz, 1H), 3.58 (dt,J=7.6, 3.9 Hz, 1H), 3.22 (s, 3H), 2.94 (s, 3H), 2.49 (tt, J=15.5, 7.7Hz, 1H), 2.28 (s, 3H), 2.09 (d, J=25.6 Hz, 1H), 1.72 (dt, J=6.0, 5.2 Hz,1H), 1.40-1.29 (m, 1H), 1.12 (d, J=6.9 Hz, 3H); ESMS (M+1)=436.29.

Compound 89 and compound 90:(7S)-4,7,8-trimethyl-2-(((1-((S)-2-phenylpropyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((1-((R)-2-phenylpropyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof intermediate A-2 and B-95 to provide the title products as a mixtureof diastereomers (Compound 85). The diastereomers were separated bychiral HPLC (Chiralpak AD-H column; 30% 1:1 MeOH:EtOH/Hexanes 0.2% DEA).

Diastereomer A: Retention time: 13.37 min; wt. 55.5 mg; 1H NMR (300 MHz,Methanol-d4) δ 7.42 (s, 1H), 7.28-7.04 (m, 6H), 4.28 (s, 2H), 4.19 (d,J=7.6 Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.04 (s, 3H), 2.17 (s, 3H), 1.33(d, J=6.8 Hz, 3H), 1.21 (d, J=7.0 Hz, 3H), 1.15 (d, J=6.1 Hz, 1H); ESMS(M+1)=406.22

Diastereomer B: Retention time: 18.23 min.; Wt. 52.6 mg; 1H NMR (300MHz, Methanol-d4) δ 7.42 (s, 1H), 7.28-7.05 (m, 6H), 4.28 (d, J=6.1 Hz,2H), 4.19 (dd, J=7.6, 2.2 Hz, 2H), 4.08 (q, J=6.8 Hz, 1H), 3.03 (s, 3H),2.17 (s, 3H), 1.33 (d, J=6.8 Hz, 3H), 1.21 (d, J=7.0 Hz, 3H). ESMS(M+1)=406.22.

Compound 95 and compound 96:(7S)-2-(((1-((S)-2-(4-fluorophenyl)propyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand(7S)-2-(((1-((R)-2-(4-fluorophenyl)propyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof intermediate A-2 and B-96 to provide the title products as a mixtureof diastereomers (Compound 86). The diastereomers were separated bychiral HPLC (Chiralpak AD-H 30% 1:1 MeOH:EtOH/Hexanes 0.2% DEA) toprovide:

Diastereomer A: Retention time: 14.96 min.; 99% ee; wt. 20 mg; 1H NMR(300 MHz, Methanol-d4) δ 7.97 (s, 1H), 7.73 (s, 1H), 7.25-7.08 (m, 2H),6.93 (dd, J=12.1, 5.3 Hz, 2H), 4.56-4.24 (m, 5H), 3.19 (s, 3H), 2.32 (s,3H), 1.54 (dd, J=6.9, 2.2 Hz, 3H), 1.30 (d, J=6.9 Hz, 3H). ESMS(M+1)=424.23.

Diastereomer B: Retention time: 18.04 min.; 99% ee; wt. 20 mg; 1H NMR(300 MHz, Methanol-d4) δ 7.97 (s, 1H), 7.73 (s, 1H), 7.25-7.08 (m, 2H),6.93 (dd, J=12.1, 5.3 Hz, 2H), 4.56-4.24 (m, 5H), 3.19 (s, 3H), 2.32 (s,3H), 1.54 (dd, J=6.9, 2.2 Hz, 3H), 1.30 (d, J=6.9 Hz, 3H). ESMS(M+1)=424.23.

Compound 92:(7S)-2-(((1-(2-(4-fluorophenyl)-2-methylpropyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-50 to provide the title product; 92% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.42 (s, 1H), 7.27 (dd, J=9.0, 5.3 Hz, 2H),6.94 (t, J=8.9 Hz, 2H), 6.86 (s, 1H), 4.42-4.26 (m, 3H), 4.23 (s, 2H),3.19 (s, 3H), 2.29 (s, 3H), 1.54 (d, J=6.9 Hz, 3H), 1.34 (d, J=4.4 Hz,6H); ESMS (M+1)=438.23.

Compound 101 and compound 102:(7S)-4,7,8-trimethyl-2-(((1-((R)-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((1-((S)-1-phenylpropan-2-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof intermediate A-2 and B-97 to provide the title products as a mixtureof the diastereomers (Compound 93). The diastereomers were separated bychiral HPLC (Chiralpak OJ-H; 30% 1:1 MeOH:EtOH (0.2% DEA)/70% Hexanes toprovide:

Diastereomer A: RT=7.55 min; wt. 164.9 mg; 1H NMR (300 MHz, Methanol-d4)δ 7.86 (s, 1H), 7.20-7.07 (m, 2H), 6.97 (d, J=6.9 Hz, 1H), 4.46 (d,J=4.3 Hz, 1H), 4.31 (q, J=6.9 Hz, 1H), 3.14 (dd, J=11.8, 5.5 Hz, 3H),2.31 (s, 2H), 1.62 (d, J=5.8 Hz, 2H), 1.52 (d, J=6.9 Hz, 2H). ESMS(M+1)=406.22.

Diastereomer B: RT=13.30 min.; wt. 141.7 mg; 1H NMR (300 MHz,Methanol-d4) δ 8.11 (s, 1H), 8.05 (s, 1H), 7.25-7.07 (m, 3H), 7.01 (dd,J=7.7, 1.6 Hz, 2H), 4.51 (s, 2H), 4.32 (q, J=6.9 Hz, 1H), 3.26-3.04 (m,5H), 2.32 (s, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.54 (d, J=6.9 Hz, 3H). ESMS(M+1)=406.22.

Compound 99:(7S)-4,7,8-Trimethyl-2-(((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one.To a solution of isopropyl(7S)-4-(4-(((4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(88 mg, 0.193 mmol) in dichloromethane (2 mL) at 0 C was added 1Msolution of BBr₃ (1 mL, 0.964 mmol) in dichloromethane. The reactionmixture was stirred for 30 minutes at 0 C, then warmed to roomtemperature and stirred for 16 hours. The reaction was quenched withmethanol (2 mL) and the solvent evaporated in vacuo. The residue waspurified by column chromatography (125 g C-18 column; gradient 5-95%ACN/water 0.1% TFA) to afford the title product (52 mg, 58%). ¹H NMR(300 MHz, Methanol-d4) δ 7.73 (s, 1H), 7.56 (s, 1H), 4.57-4.43 (m, 3H),4.30 (q, J=6.9 Hz, 1H), 3.55 (dd, J=13.3, 3.2 Hz, 2H), 3.27 (s, 3H),3.19 (td, J=13.0, 4.6 Hz, 2H), 2.34-2.16 (m, 7H), 1.53 (d, J=6.9 Hz,3H); ESMS (M+1)=371.24. The following compounds (Compounds 124 and 125)were prepared by the general procedure provided.

To a suspension of(7S)-4,7,8-trimethyl-2-(((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(Compound 99; 60 mg, 0.162 mmol) and DIPEA (85 uL, 0.486 mmol) indichloromethane (1 ml) was added the appropriate acid chloride (0.162mmol). The resulting solution was stirred for 16 hours at roomtemperature then quenched with water (2 ml). The organic layer wasseparated and the solvent evaporated under a stream of nitrogen. Theresidue was purified by reverse phase chromatography (C18 column;gradient 5-95% ACN/water 0.1% TFA). The desired fraction were evaporatedand the purified material dissolved in 1 ml of methanol and passedthrough a PL-HCO3 resin cartridge to provide the desired product.

Compound 124:(7S)-4,7,8-Trimethyl-2-(((1-(1-(3,4,5-trifluorobenzoyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

Obtained from the reaction of(7S)-4,7,8-trimethyl-2-(((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-oneand 3,4,5-trifluorobenzoyl chloride to provide 15 mg of the titleproduct. ¹H NMR (300 MHz, Methanol-d4) δ 7.65 (s, 1H), 7.48 (s, 1H),7.30 (dd, J=7.7, 6.6 Hz, 2H), 5.48 (s, 2H), 4.68 (bs, 1H), 4.51-4.33 (m,3H), 4.07 (q, J=6.8 Hz, 1H), 3.77 (bs, 1H), 3.07 (s, 3H), 2.18 (s, 3H),2.13-1.92 (m, 4H); ESMS (M+1)=529.16.

Compound 125:(7S)-2-(((1-(1-(4-Fluorobenzoyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

Obtained from the reaction of(7S)-4,7,8-trimethyl-2-(((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-oneand 4-fluorobenzoyl chloride to provide 6.6 mg of the title product. ¹HNMR (300 MHz, Methanol-d4) δ 7.66 (s, 1H), 7.55-7.44 (m, 3H), 7.20 (t,J=8.8 Hz, 2H), 4.53-4.33 (m, 4H), 4.07 (q, J=6.9 Hz, 1H), 3.85 (bs, 1H),3.07 (s, 3H), 2.18 (s, 3H), 2.01 (s, 4H), 1.33 (d, J=6.8 Hz, 3H); ESMS(M+1)=493.24.

Compound 130:(7S)-2-(((1-(1-(4-fluorophenyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

To a suspension of(7S)-4,7,8-trimethyl-2-(((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(Compound 99; 100 mg, 0.270 mg) and 1-bromo-4-fluorobenzene (57.0 mg,0.324 mmol) in t-butanol (3 mL) at RT was added NaOtBu (540 mL, 2M inTHF, 1.08 mmol). The solution was degassed for 10 min with N₂ andt-BuXPhos Palladacycle (19 mg, 0.027 mmol) was added. The reactionmixture was warmed to 50° C. and stirred for 16 hours. The cooledsolution was diluted with DMSO (1 mL) and filtered through Florisil andpurified by column chromatography (C-18 column; gradient 5-95% ACN/water0.1% TFA). The desired fraction were evaporated in vacu, dissolved inmethanol and free based through a PL-HCO₃ MP resin cartridge, andevaporated to afford the desired product (2.1 mg, 1.6%) as a clearglass. ¹H NMR (300 MHz, Methanol-d4) δ 7.48 (s, 1H), 7.35 (s, 1H), 7.16(dd, J=9.1, 5.1 Hz, 2H), 7.03 (t, J=8.8 Hz, 2H), 4.99 (s, 2H), 4.18 (m,1H), 4.07 (dd, J=13.8, 6.9 Hz, 1H), 3.20-3.03 (m, 3H), 2.96 (s, 3H),2.76-2.62 (m, 2H), 2.17 (s, 3H), 2.01 (d, J=12.5 Hz, 2H), 1.90-1.72 (m,3H), 1.33 (d, J=6.8 Hz, 3H); ESMS (M+1)=465.24.

Compound 179:(7S)-2-(((1-(1-(3,5-difluorophenyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

In a sealed tube was placed 1,3,5-Trifluorobenzene (Compound 99; 325 mg,2.45 mmol) was added to a solution of(7S)-4,7,8-trimethyl-2-(((1-(piperidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(140 mg, 0.3779 mmol) in DMSO (1 mL) and triethylamine (0.5 ml) andheated at 70° C. for 20 hours. Reaction incomplete so heated at 170° C.for 2 hours. The reaction was cooled to room temperature and poured into75 ml of water and extracted with ethyl acetate (3×75 ml). The combinedextracts were washed with brine, dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo. The crude product was purified bycolumn chromatography (SiO₂) eluting with a gradient of 0-10% methanol(0.1% ammonia) in dichloromethane to afford the title product, wt. 68 mg(35% yield). ¹H NMR (400 MHz, Methanol-d4) δ 7.65 (s, 1H), 7.47 (s, 1H),6.53 (d, J=9.1 Hz, 2H), 6.27 (t, J=9.1 Hz, 1H), 4.45-4.19 (m, 3H), 4.09(q, J=6.9 Hz, 1H), 3.87 (d, J=13.1 Hz, 2H), 3.09 (s, 3H), 2.95 (dd,J=17.9, 7.0 Hz, 2H), 2.65 (d, J=1.0 Hz, 5H), 2.26-1.96 (m, 6H), 1.35 (d,J=6.8 Hz, 3H); ESMS (M+1)=483.44. Chiral HPLC(Chiral PAK IC column,4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1% diethylamine):Rt=9.473 minutes; 97% ee.

Compound 131 and 132:(7S)-2-[[1-[(2S)-2-(4-fluorophenyl)-2-hydroxy-ethyl]pyrazol-4-yl]methylamino]-4,7,8-trimethyl-5,7-dihydropteridin-6-oneand(7S)-2-[[1-[(2R)-2-(4-fluorophenyl)-2-hydroxy-ethyl]pyrazol-4-yl]methylamino]-4,7,8-trimethyl-5,7-dihydropteridin-6-one

Sodium borohydride (36 mg, 0.9446 mmol) was added to a solution of(7S)-2-[[1-[2-(4-fluorophenyl)-2-oxo-ethyl]pyrazol-4-yl]methylamino]-4,7,8-trimethyl-5,7-dihydropteridin-6-one(200 mg, 0.4723 mmol) in methanol (10 mL) at room temperature. Thereaction was stirred for 2 hours followed by the addition of 2 ml ofacetone to quench the reaction. The solvent was removed in vacuo and theresulting crude was taken into 5 ml of water and extracted with ethylacetate (2×25 ml). The combined extracts were dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to afford the crudeproduct that was purified by column chromatography eluting with agradient of 0-20% methanol in dichloromethane. The desired fractionswere evaporated in vacuo to afford 135 mg (62% yield) of the titleproducts as a mixture of diastereomers (Compound 100). 1H NMR (300 MHz,DMSO-d6) δ 9.83 (s, 1H), 7.47 (d, J=0.6 Hz, 1H), 7.33 (d, J=0.7 Hz, 1H),7.32-7.25 (m, 2H), 7.09 (td, J=9.0, 0.9 Hz, 2H), 6.53 (t, J=5.9 Hz, 1H),5.64 (d, J=4.7 Hz, 1H), 4.89 (q, J=5.8 Hz, 1H), 4.25-4.07 (m, 4H),4.05-3.91 (m, 1H), 2.95 (s, 3H), 2.13 (s, 3H), 1.19 (d, J=6.8 Hz, 3H).ESMS (M+1)=426.36.

The diastereomers were separated by chiral HPLC (OJ-H column, 20×250 mm;70% Hexanes/15% methanol/15% ethanol/0.2% diethylamine, isocratic; 20ml/min flow rate) to provide 18 mg of each diastereomer:

Diastereomer A: Rt 8.897 mins.; 90.8% ee

Diastereomer B: Rt 11.245 mins.; 86% ee.

Compound 128:(7S)-2-(((1-(2-(4-fluorophenyl)-2-hydroxypropyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

To a solution of(7S)-2-[[1-[2-(4-fluorophenyl)-2-oxo-ethyl]pyrazol-4-yl]methylamino]-4,7,8-trimethyl-5,7-dihydropteridin-6-one(125 mg, 0.29 mmol) in dry THE was added MeMgBr (405.5 mg, 393.7 μL of 3M, 1.18 mmol) at −78° C. The reaction was stirred at −78° C. for 2hours. The reaction was warmed to room temperature and stirred for 24hours. The reaction was quenched with a saturated ammonium chloride andextracted with dichloromethane. The extracts were evaporated in vacuo toafford the crude product. The product and unreacted starting materialwere not separable so the crude was taken up into methanol and 0.3 ml ofhydrazine was added to the solution and stirred for 2 hours. The mixturewas evaporated in vacuo and the crude product purified by columnchromatography eluting with a gradient of dichloromethane to 0-20%methanol in dichloromethane. The desired fractions were evaporated toprovide the desired product, wt. 6.9 mg (5% yield). 1H NMR (300 MHz,DMSO-d6) δ 10.48 (s, 1H), 7.79 (brs, 1H), 7.45 (s, 1H), 7.39 (dd, J=8.7,5.6 Hz, 2H), 7.32 (s, 1H), 7.04 (t, J=8.9 Hz, 2H), 5.48 (brs, 1H),4.39-4.30 (m, 2H), 4.24 (s, 2H), 3.15 (s, 3H), 2.26 (s, 3H), 1.42 (d,J=6.9 Hz, 3H), 1.36 (d, J=1.1 Hz, 3H); ESMS (M+1)=440.32.

Compound 50:(7S)-2-(((1-(3,5-difluoro-4-hydroxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one(34 mg, 0.07781 mmol) was taken into 10 ml of dichloromethane. A 1 Msolution of boron tribromide (400 ul; 0.4 mmol) in dichloromethane wasadded to the solution and stirred at room temperature for 18 hours.Methanol was added to the mixture to quench the reaction. The solventwas evaporated in vacuo to provide a residue that was dissolved in DMSO,filtered, and purified by reverse phase preparative HPLC(Acetonitrile/water/TFA). The desired fractions were neutralized bypassing through a PL-HCO3 MPSPE cartridge. Evaporation of the solventafforded 14 mg of the desired product. 1H NMR (300 MHz, Methanol-d4) δ7.64 (d, J=0.8 Hz, 1H), 7.52 (d, J=0.8 Hz, 1H), 7.40 (s, 1H), 6.83-6.74(m, 2H), 5.20 (s, 2H), 4.40 (s, 2H), 4.14 (q, J=6.9 Hz, 1H), 3.08 (s,3H), 1.42 (d, J=6.9 Hz, 3H); ESMS (M+H)=416.26.

Compound 73 and 74:(7S)-2-(((1-(4-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand(7S)-2-(((1-(4-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof intermediate A-2 and B-98 to provide the title products as a mixtureof the regioisomers. The mixture was inseparable by columnchromatography. The regioisomers were separated by SFC (column: AD-H,110×250 mm; 40% methanol (0.2% diethylamine/60% CO₂) to provide eachindividual regioisomer.

Peak A: Rt 0.783 minutes. Major, (93 mg, 46% yield) 1H NMR (300 MHz,CDCl₃) δ 8.91-8.32 (m, 1H), 7.27 (d, J=5.4 Hz, 1H), 7.23-7.11 (m, 2H),7.02 (dd, J=9.6, 7.6 Hz, 2H), 5.17 (s, 2H), 4.69 (t, J=5.3 Hz, 1H), 4.35(d, J=5.4 Hz, 2H), 4.06 (q, J=6.8 Hz, 1H), 3.03 (s, 3H), 2.27 (s, 3H),2.24 (s, 3H), 1.40 (d, J=6.9 Hz, 3H). ESMS (M+1)=410.16.

Peak B: Rt 1.595 minutes. Minor, (53 mg, 26% yield) 1H NMR (400 MHz,CDCl₃) δ 8.97 (s, 1H), 7.49 (s, 1H), 7.14-6.91 (m, 4H), 5.23 (s, 2H),4.81-4.61 (m, 1H), 4.34 (d, J=5.3 Hz, 2H), 4.06 (q, J=6.8 Hz, 1H), 3.05(s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 1.39 (d, J=6.8 Hz, 3H). ESMS(M+1)=449.32.

2B. Preparation of Compounds of Table 5

TABLE 5 Compound No. Ring A Method Compound 138

A Compound 139

A Compound 158

A Compound 159

A Compound 160

A Compound 189

A Compound 190

A Compound 191

A Compound 192

A Compound 193

A

Compound 138:(7S)-2-(((1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-85 to provide the title product, 48% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.58 (s, 1H), 7.47 (s, 1H), 5.11 (s, 2H),4.36 (s, 2H), 4.07 (q, J=6.9 Hz, 1H), 3.04 (s, 3H), 2.36 (s, 3H), 2.17(s, 3H), 2.06 (s, 3H), 1.32 (d, J=6.8 Hz, 3H); ESMS (M+H)=397.15. ChiralHPLC(ChiralPAK IC column; 200% methanol/30% ethanol/50% hexanes,isocratic) Rt 13.781 mins.; 9800 ee.

Compound 139:(7S)-2-(((1-((1,3-dimethyl-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-86 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.49 (s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 5.09 (s,1H), 4.35 (s, 2H), 4.06 (q, J=6.8 Hz, 1H), 3.77 (s, 3H), 3.03 (s, 3H),2.16 (s, 3H), 2.08 (s, 3H), 1.32 (d, J=6.8 Hz, 3H); ESMS (M+H)=396.16.Chiral HPLC(ChiralPAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic) Rt 15.157 mins.; 97% ee.

Compound 158:(7S)-2-(((1-((3-ethyl-5-methylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-87 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.54 (s, 1H), 7.46 (s, 1H), 5.10 (s, 2H), 4.36 (s,2H), 4.07 (q, J=6.8 Hz, 1H), 3.04 (s, 3H), 2.47 (q, J=7.6 Hz, 2H), 2.36(s, 3H), 2.17 (s, 3H), 1.33 (d, J=6.8 Hz, 3H), 1.05 (t, J=7.6 Hz, 3H);ESMS (M+H)=411.29.

Compound 159:(7S)-4,7,8-trimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-88 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.69 (s, 1H), 7.60 (s, 1H), 7.51 (s, 1H), 5.25 (s,2H), 4.54-4.41 (m, 2H), 4.30 (q, J=6.9 Hz, 1H), 3.90 (s, 3H), 3.23 (s,3H), 2.28 (s, 3H), 1.52 (d, J=6.9 Hz, 3H). ESMS (M+H)=450.22.

Compound 160:(7S)-4,7,8-trimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-89 to provide the title product. 1H NMR (300MHz, DMSO-d6) δ 9.81 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H), 6.68-6.51 (m,2H), 5.44 (s, 2H), 4.30-4.12 (m, 2H), 3.99 (q, J=6.8 Hz, 1H), 3.88 (s,3H), 2.93 (s, 3H), 2.12 (s, 3H), 1.18 (d, J=6.8 Hz, 3H); ESMS(M+H)=450.17; Chiral HPLC(ChiralPAK IC column; 20% methanol/30%ethanol/50% hexanes, isocratic) Rt 7.083 mins.; 97% ee. [α]_(D) ²⁰+48.2°(c=0.71, 1:1 methanol/dichloromethane).

Compound 189:(7S)-2-(((1-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-90 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 8.11 (s, 1H), 7.50 (s, 1H), 7.44-7.39 (m, 1H), 6.46 (s,1H), 5.51 (s, 1H), 5.23 (s, 2H), 4.46-4.36 (m, 2H), 4.23 (q, J=7.2 Hz,2H), 4.08 (q, J=6.9 Hz, 1H), 3.06 (s, 3H), 2.24 (s, 3H), 1.46 (t, J=7.2Hz, 3H), 1.42 (d, J=6.9 Hz, 3H); ESMS (M+H)=464.26. ChiralHPLC(ChiralPAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic) Rt 6.691 mins.; 92% ee.

Compound 190:(7S)-4,7,8-trimethyl-2-(((1-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-91 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 8.05 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 6.54 (s, 1H),5.25 (s, 2H), 4.45 (d, J=5.8 Hz, 2H), 4.13 (q, J=6.9 Hz, 1H), 3.98 (s,3H), 3.12 (s, 3H), 2.28 (s, 3H), 1.48 (d, J=6.8 Hz, 3H). ESMS(M+H)=450.26. Chiral HPLC(ChiralPAK IC column; 20% methanol/30%ethanol/50% hexanes, isocratic) Rt 8.817 mins.; 95.6% ee.

Compound 191:(7S)-2-(((1-((1-ethyl-1H-imidazol-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-92 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 8.38 (s, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 6.98 (d, J=5.7Hz, 1H), 6.89 (d, J=1.2 Hz, 1H), 5.35 (s, 2H), 4.34 (t, J=7.4 Hz, 2H),4.04 (q, J=6.9 Hz, 1H), 3.97 (q, J=7.3 Hz, 2H), 3.01 (s, 3H), 2.21 (s,3H), 1.38 (d, J=6.9 Hz, 3H), 1.19 (t, J=7.3 Hz, 3H); ESMS (M+H)=396.3.Chiral HPLC(ChiralPAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic) Rt 17.014 mins.; 99% ee.

Compound 192:(7S)-4,7,8-trimethyl-2-(((1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-93 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.64 (s, 1H), 7.49 (s, 1H), 6.95-6.86 (m, 1H), 6.49(d, J=3.4 Hz, 1H), 5.35 (s, 2H), 4.39 (s, 2H), 4.07 (q, J=6.8 Hz, 1H),3.05 (s, 3H), 2.17 (s, 3H), 1.33 (d, J=6.9 Hz, 3H); ESMS (M+H)=436.29.Chiral HPLC(ChiralPAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic) Rt 6.85 mins.; 91.6% ee.

Compound 193:(7S)-2-(((1-((2,5-dimethyloxazol-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-94 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.58 (s, 1H), 7.44 (s, 1H), 5.08 (s, 2H), 4.37 (s,2H), 4.06 (q, J=6.8 Hz, 1H), 3.05 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H),2.17 (s, 3H), 1.32 (d, J=6.8 Hz, 3H); ESMS (M+H)=397.31. ChiralHPLC(ChiralPAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic) Rt 11.821 mins.; 92% ee.

Compound 40 R₆═CH3:(7S)-2-(((5-(4-Fluorophenyl)furan-2-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediate A-2 and (5-(4-fluorophenyl)furan-2-yl)methanamine toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.71-7.59 (m,2H), 7.16-7.03 (m, 2H), 6.63 (d, J=3.3 Hz, 1H), 6.33 (dt, J=3.3, 0.8 Hz,1H), 4.63-4.56 (m, 2H), 4.14 (q, J=6.9 Hz, 1H), 3.13 (s, 3H), 2.22 (s,3H), 1.39 (d, J=6.9 Hz, 3H); ESMS (M+1)=382.31.

Compound 43 R₆═H:(7S)-2-(((5-(4-fluorophenyl)furan-2-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediate A-1 and (5-(4-fluorophenyl)furan-2-yl)methanamine toprovide the title product. 1H NMR (300 MHz, CDCl₃) δ 7.68-7.56 (m, 2H),7.40 (s, 1H), 7.13-7.00 (m, 2H), 6.51 (d, J=3.3 Hz, 1H), 6.36-6.28 (m,1H), 4.69-4.60 (m, 2H), 4.14 (q, J=6.9 Hz, 1H), 3.13 (s, 3H), 1.50 (d,J=6.9 Hz, 3H); ESMS (M+1)=368.26.

Compound 59:(7S)-4,7,8-trimethyl-2-(((4-phenylthiazol-2-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and (4-phenylthiazol-2-yl)methanamine to provide thetitle product. ESMS (M+1)=381.33.

Compound 60:(S)-4,7,8-trimethyl-2-(((2-(piperidin-1-yl)pyridin-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and (2-(piperidin-1-yl)pyridin-4-yl)methanamine toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.85 (d,J=6.6 Hz, 1H), 7.34 (s, 1H), 6.94 (d, J=6.5 Hz, 1H), 4.71 (s, 2H), 4.28(q, J=6.9 Hz, 1H), 3.71 (d, J=5.5 Hz, 4H), 3.14 (s, 3H), 2.34 (s, 3H),1.76 (s, 6H), 1.51 (d, J=6.9 Hz, 3H); ESMS (M+1)=382.32.

Compound 62:(S)-4,7,8-trimethyl-2-(((2-morpholinopyridin-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and (2-morpholinopyridin-4-yl)methanamine to providethe title product. ESMS (M+1)=384.39.

2C. Preparation of Compounds of Table 6

TABLE 6 Compound # L₁-Ring A R₆ Compound 161

Me Compound 162

Me Compound 163

Me Compound 164

H Compound 165

H Compound 166

H

Compound 161:(7S)-4,7,8-trimethyl-2-(((1-(5-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-153 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.77-8.67 (m, 2H), 7.85 (d, J=0.8 Hz, 1H), 4.57 (dd,J=6.0, 2.5 Hz, 2H), 4.20 (q, J=6.8 Hz, 1H), 3.24 (s, 3H), 2.79 (t, J=0.8Hz, 3H), 2.36 (s, 3H), 1.55 (d, J=6.9 Hz, 3H); ESMS (M+1)=448.19.

Compound 162:(7S)-2-(((1-((5-fluoropyrimidin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-151 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.60 (d, J=0.5 Hz, 2H), 7.57 (dd, J=5.6, 0.8 Hz, 2H), 5.53(d, J=1.0 Hz, 2H), 4.48 (d, J=5.7 Hz, 2H), 4.11 (q, J=6.9 Hz, 1H), 3.10(s, 3H), 2.27 (s, 3H), 1.45 (d, J=6.9 Hz, 3H); ESMS (M+1)=398.26.

Compound 163:(7S)-4,7,8-trimethyl-2-(((1-((2-methylpyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-152 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.54 (s, 2H), 7.55-7.46 (m, 2H), 5.24 (s, 2H), 4.43 (s,2H), 4.11 (q, J=6.9 Hz, 1H), 3.11 (s, 3H), 2.72 (s, 3H), 2.27 (s, 3H),1.46 (d, J=6.9 Hz, 3H); ESMS (M+1)=393.89.

Compound 164:(7S)-7,8-dimethyl-2-(((1-(5-methyl-2-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-1 and B-153 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.75-8.65 (m, 2H), 7.84 (d, J=0.9 Hz, 1H), 7.36 (s, 1H),4.56-4.49 (m, 2H), 4.14 (q, J=6.9 Hz, 1H), 3.18 (s, 3H), 2.77 (t, J=0.8Hz, 3H), 1.50 (d, J=6.9 Hz, 3H); ESMS (M+1)=434.27.

Compound 165:(7S)-2-(((1-((5-fluoropyrimidin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-1 and B-151 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.63-8.56 (m, 2H), 7.66-7.53 (m, 3H), 5.54 (d, J=1.0 Hz,2H), 4.50 (d, J=5.6 Hz, 2H), 4.19 (q, J=6.9 Hz, 1H), 3.16 (s, 3H), 1.52(d, J=7.0 Hz, 3H); ESMS (M+1)=384.21.

Compound 166:(7S)-7,8-dimethyl-2-(((1-((2-methylpyrimidin-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-1 and B-152 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.57 (s, 2H), 7.69 (s, 1H), 7.62-7.50 (m, 2H), 5.28 (d,J=2.4 Hz, 2H), 4.47 (d, J=5.6 Hz, 2H), 4.20 (q, J=6.8 Hz, 1H), 3.17 (s,3H), 2.73 (s, 3H), 1.54 (d, J=7.0 Hz, 3H); ESMS (M+1)=380.25.

2D. Preparation of Compounds of Table 7 General Scheme

TABLE 7     Comp #

    R¹     R²     R³     R⁴     R⁶   Prep Method Comp 136

H Me Me H Me A Comp 177

Me Me Me H Me B Comp 77

H Me Me H Me A Comp 82

Me Me Me H Me B Comp 94

H Me Me H Me A Comp 129

Me Me Me H Me C Comp 135

H Me Me H Me C Comp 167

H Me Me H Me C Comp 168

H Me Me H Me C Comp 10

H Me Me H Me D Comp 173

H Me Me H Me A Comp 174

H Me Me H Me A Comp 175

H Me Me H Me A Comp 176

H Me Me H Me A Comp 178

H Me Me H Me B Comp 180

H Me Me H Me A Comp 182

H Me Me H Me A Comp 183

H Me Me H Me A Comp 184

H Me Me H Me B Comp 187

H Me Me H Me B Comp 188

H Me Me H Me A Comp 194

H Me Me H Me See procedure Comp 195

H Me Me H H B Comp 196

H Me Me H Me D Comp 197

H Me Me H Me A Comp 198

H Me Me H Me See procedure Comp 199

H Me Me H Me A Comp 185

H Me Me H Me B Comp 200

H Me Me H Me B Comp 201

H Me Me H Me B Comp 12

H Me Me H Me B Comp 202

H Me Me H Me B Comp 203

H Me Me H Me B Comp 204

H Me Me H Me B Comp 206

H Me Me H Me A Comp 207

H Me Me H Me B Comp 210

H Me Me H Me A Comp 211

H Me Me H Me A Comp 209

H Me Me H Me A Comp 218

H Me Me H Me A Comp 215

H Me Me H Me A Comp 213

H Me Me H Me A Comp 208

H Me Me H Me B Comp 205

Me Me Me H Me B Comp 385

H i-Pr Me H Me A Comp 220

H Me n-Pr H Me A Comp 383

H Me i-Pr H Me A Comp 384

H Me i-Pr H Me A Comp 400

H CD3 Me H Me A Comp 386

H Me c-Pr H Me A Comp 387

H Me Me H Me A Comp 388

H Me Me H Me A Comp 238

H Me Me Me Me A Comp 237

Me Me Me Me H A Comp 236

Me Me Me Me H A Comp 186

H Me Et H Me A Comp 390

H Me Me H Me A Comp 394

H Me Et H Me A Comp 389

H Me Et H Me A Comp 395

H Et Me H Me A Comp 396

H Me c-Pr H Me A Comp 397

H Me i-Pr H Me A Comp 398

H Me Spiro-c-Bu Me A Comp 239

H Me Spiro-c-Pr Me A

Compound 136:(7S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-111-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

A mixture of (7S)-2-Chloro-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(A-2; 40 g, 176.5 mmol),(1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride (B-52; 78.4 g, 212 mmol), and sodium tert-butoxide (59.4g, 618 mmol) was taken into tert-butanol (640 ml) and purged withnitrogen. tfluXPhos Pd Gen 1(2.42 g, 3.53 mmol) was added to the mixtureand an exotherm was observed (temperature rose to 48° C.). The reactiontemperature was maintained at 50° C. for 30 minutes. The solvent wasremoved under vacuum and the resulting residue was taken into water (1liter) and extracted with dichloromethane (2×600 ml). The extracts werewashed with brine, dried over anhydrous sodium sulfate, and filtered.Celite (110 g) was added to the filtrate and the solvent evaporated invacuo. The solid residue was dry loaded onto 1.5 kg of silica gel andeluted with a gradient of 0-20% methanol in dichloromethane. The desiredfractions were evaporated in vacuo to afford a green foam. The foamproduct was dissolved in 600 ml of dichloromethane and 35 g f BiotageMp-TMT resin was added and stirred overnight. The solvent was filteredthrough a pad of Florisil and washed with ethyl acetate. The filtratewas evaporated invacuo. Heptane ((800 ml) was added to the resultingmaterial and stirred for 30 minutes followed by vacuum filtration andsubsequent washing with heptane. The material washed with heptane wasthen dried in a vacuum oven at 55° C. to provide the title product, 64 g(80.4% yield). ¹H NMR (300 MHz, CDCl₃) δ 8.61 (s, 1H), 7.68 (t, J=1.4Hz, 2H), 7.57 (d, J=0.7 Hz, 1H), 7.44 (d, J=0.8 Hz, 1H), 5.38 (s, 2H),4.95 (s, 1H), 4.48-4.38 (m, 2H), 4.09 (q, J=6.8 Hz, 1H), 3.06 (s, 3H),2.22 (s, 3H), 1.42 (d, J=6.9 Hz, 3H). ESMS (M+1)=447.3; Chiral HPLC(ChiralPAK IC column; 20% MeOH/30% EtOH/50% hexanes (0.1% Diethylamine),isocratic) Rt 7.548 (98.6% ee). [α]_(D)=45.5° (c=1, methanol);mp=175-176° C.

Compound 177:(7S)-4,5,7,8-tetramethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-52 to provide the title compound. Yield, 20%. 1HNMR (300 MHz, DMSO-d6) δ 8.66-8.60 (m, 1H), 7.97-7.81 (m, 2H), 7.77 (s,1H), 7.44 (s, 1H), 6.83 (t, J=6.0 Hz, 1H), 5.45 (s, 2H), 4.25 (dd,J=6.0, 2.3 Hz, 2H), 4.01 (q, J=6.7 Hz, 1H), 3.18 (s, 3H), 2.92 (s, 3H),2.27 (s, 3H), 1.05 (d, J=6.8 Hz, 3H); ESMS (M+1)=461.43; Chiral HPLC(ChiralPAK IC column; 20% MeOH/30% EtOH/50% hexanes (0.1% Diethylamine),isocratic) Rt 10.137 mins. (99% ee).

Compound 77:(7S)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-53 to provide the title compound; 88 mg, yield38.31%; 1H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.05 (dd, J=2.4, 1.1 Hz,1H), 7.58 (ddd, J=8.7, 7.6, 2.6 Hz, 1H), 7.45 (s, 1H), 7.31 (s, 1H),6.83 (dd, J=8.5, 2.9 Hz, 1H), 5.18 (s, 2H), 5.06-4.89 (m, 1H), 4.34 (dd,J=5.8, 2.2 Hz, 2H), 3.99 (q, J=6.8 Hz, 1H), 2.96 (d, J=0.7 Hz, 3H), 2.17(d, J=0.8 Hz, 3H), 1.32 (d, J=6.9 Hz, 3H). ESMS (M+1)=397.11. ChiralHPLC (ChiralPAK IC column; 20% MeOH/30% EtOH/50% hexanes (0.1%Diethylamine), isocratic) Rt 3.751 mins. (98% ee). [α]_(D)=47.0°(c=0.97, methanol).

Compound 82:(7S)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-53 to provide the title compound; Yield, 58.05%;¹H NMR (300 MHz, CDCl₃) δ 8.23-8.07 (m, 1H), 7.67 (td, J=7.9, 2.6 Hz,1H), 7.55 (s, 1H), 7.41 (s, 1H), 6.92 (dd, J=8.4, 3.0 Hz, 1H), 5.29 (d,J=11.6 Hz, 2H), 5.20 (s, 1H), 4.44 (d, J=5.8 Hz, 2H), 4.02 (q, J=6.8 Hz,1H), 3.30 (s, 3H), 3.02 (s, 3H), 2.37 (s, 3H), 1.21 (d, J=6.9 Hz, 3H).ESMS (M+1)=411.27; Chiral HPLC (ChiralPAK IC column; 20% MeOH/30%EtOH/50% hexanes (0.1% Diethylamine), isocratic) Rt 16.201 mins (65%ee).

Compound 94:(7S)-2-(((1-((6-fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure A via reaction of A-2 andB-54 to provide the title compound; Yield 32%; 1H NMR (300 MHz, CDCl₃) δ7.84 (s, 1H), 7.45 (s, 1H), 7.25 (s, 1H), 6.76 (s, 1H), 5.21 (s, 2H),4.33 (s, 2H), 3.99 (q, J=6.7 Hz, 1H), 2.98 (s, 3H), 2.24 (s, 3H), 2.13(s, 3H), 1.32 (d, J=6.8 Hz, 3H); ESMS (M+1)=411.32.

Compound 129:(7S)-2-(((1-((6-isopropoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

Sodium hydride (12.48 mg, 0.5200 mmol) was added to a solution of(S)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(44 mg, 0.1040 mmol) in isopropanol (1.5 mL). The mixture was heated at60° C. for 3 hours. The reaction was quenched with saturated NH4Clsolution and extracted with ethyl acetate (2×15 mL). The combinedorganic extracts was washed with brine, dried over MgSO4 andconcentrated in vacuo to afford the crude product, which was purified bycolumn chromatography (SiO₂) (eluting with a gradient of 0-6% methanolin dichloromethane to provide the desired product. Yield, 87.2%. ¹H NMR(300 MHz, CDCl₃) δ 7.97 (dd, J=2.5, 0.8 Hz, 1H), 7.46-7.39 (m, 1H), 7.36(dd, J=8.6, 2.6 Hz, 1H), 7.26 (d, J=0.8 Hz, 1H), 6.56 (dd, J=8.5, 0.7Hz, 1H), 5.20 (dt, J=12.4, 6.1 Hz, 1H), 5.08 (s, 2H), 4.92 (t, J=5.7 Hz,1H), 4.33 (d, J=5.7 Hz, 2H), 3.91 (q, J=6.9 Hz, 1H), 3.21 (s, 3H), 2.91(s, 3H), 2.26 (s, 3H), 1.25 (d, J=6.2 Hz, 6H), 1.11 (d, J=6.9 Hz, 3H).ESMS (M+1)=451.35.

The following three compounds, Compound 135, 167, and 168, were preparedby the general procedure as reported for Compound 129.

Compound 135:(7S)-2-(((1-((6-isopropoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by the procedure reported for Compound 129 viareaction of(7S)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand isopropanol to provide the title compound; Yield, 93%; 1H NMR (300MHz, CDCl₃) δ 9.01 (s, 1H), 8.09-7.97 (m, 1H), 7.50 (d, J=0.8 Hz, 1H),7.43 (dd, J=8.5, 2.6 Hz, 1H), 7.33 (d, J=0.8 Hz, 1H), 6.64 (dd, J=8.5,0.7 Hz, 1H), 5.28 (p, J=6.2 Hz, 1H), 5.16 (s, 2H), 4.92 (t, J=5.7 Hz,1H), 4.40 (d, J=5.7 Hz, 2H), 4.05 (q, J=6.9 Hz, 1H), 3.02 (s, 3H), 2.24(s, 3H), 1.39 (d, J=6.9 Hz, 3H), 1.33 (d, J=6.2 Hz, 6H). ESMS(M+1)=437.25.

Compound 167:(7S)-2-(((1-((6-(tert-butoxy)-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure reported for Compound 129 viareaction of t-butanol and(S)-2-(((1-((6-fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneto provide the title compound; Yield, 0.7%. 1H NMR (300 MHz, CDCl₃) δ7.88 (s, 1H), 7.49 (d, J=0.8 Hz, 1H), 7.31-7.25 (m, 1H), 6.53-6.44 (m,1H), 5.17 (s, 2H), 4.40 (d, J=5.6 Hz, 2H), 4.12 (q, J=6.9 Hz, 1H), 3.11(s, 3H), 2.32 (s, 3H), 2.13 (d, J=0.8 Hz, 3H), 1.57 (s, 9H), 1.48 (d,J=6.9 Hz, 3H); ESMS (M+1)=465.44.

Compound 168:(7S)-2-(((1-((6-isopropoxy-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure reported for Compound 129 viareaction of isopropanol and(7S)-2-(((1-((6-fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(Compound 94) to provide the title compound. Yield, 1.4%. 1H NMR (300MHz, CDCl₃) δ 8.92 (s, 1H), 7.88 (s, 1H), 7.46 (d, J=0.8 Hz, 1H),7.32-7.22 (m, 1H), 6.54-6.42 (m, 1H), 5.26-5.18 (m, 1H), 5.16 (s, 2H),4.38 (d, J=5.6 Hz, 2H), 4.12 (q, J=6.9 Hz, 1H), 3.12 (s, 3H), 2.32 (s,3H), 2.13 (d, J=0.8 Hz, 3H), 1.49 (d, J=6.9 Hz, 3H), 1.30 (d, J=6.2 Hz,5H). ESMS (M+1)=451.44.

Compound 10:(7S)-4,7,8-trimethyl-2-(((1-((6-(methylamino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(Method D)

To a solution of(7S)-2-[[1-[(6-fluoro-3-pyridyl)methyl]pyrazol-4-yl]methylamino]-4,7,8-trimethyl-5,7-dihydropteridin-6-one(100 mg, 0.2486 mmol) in MeOH (2 mL) was added methylamine (68.26 μL of4.37 M, 0.2983 mmol), the mixture was heated in a sealed vessel over theweekend. LCMS indicted completion of the reaction. After removal of thesolvent, the crude material was purified on reverse phase C18chromatography (ACN/H2O 0-50% in 20 cv) to give desired product. Yield,60%. 1H NMR (300 MHz, CDCl₃) δ 8.03-7.90 (m, 1H), 7.83 (q, J=8.2 Hz,2H), 7.64 (q, J=6.3 Hz, 1H), 7.03 (h, J=7.3, 6.7 Hz, 1H), 5.38-5.18 (m,2H), 4.53 (q, J=6.3 Hz, 2H), 4.31 (tt, J=6.8, 3.4 Hz, 1H), 3.03 (q,J=6.9 Hz, 3H), 2.30 (q, J=6.6 Hz, 3H), 1.61-1.40 (m, 3H). ESI-MS m/zcalc. 407.44, found 408.35.

Compound 173:(7S)-4,7,8-trimethyl-2-(((1-((6-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-55 to provide the title compound; Yield 82.5%.1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.36 (s, 1H), 7.73 (s, 1H),7.52 (dd, J=7.9, 2.4 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 5.26(s, 2H), 4.30 (d, J=5.8 Hz, 2H), 4.16 (q, J=6.9 Hz, 1H), 3.04 (s, 3H),2.43 (s, 3H), 2.19 (s, 3H), 1.30 (d, J=6.8 Hz, 3H). ESMS (M+1)=393.31.

Compound 174 and compound 175:(7S)-4,7,8-Trimethyl-2-(((1-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-Trimethyl-2-(((1-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof intermediates A-2 and B-150 to provide a mixture of diastereomers(Compound 172); 64% yield. The diastereomers were separated by SFC (ICColumn, 10×250 mm; 40% ethanol (0.2% diethylamine)/60% CO2, Isocratic;10 ml/min) to provide the diastereomer A and distereomer B.

Diastereomer A: Chiral HPLC(Chiral PAK IC column, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine): Rt=6.81 mins.; 99%ee. 1H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.62 (s, 1H), 7.86 (d,J=1.5 Hz, 2H), 7.79 (d, J=0.8 Hz, 1H), 7.44 (d, J=0.8 Hz, 1H), 6.58(brs, 1H), 5.77 (q, J=7.1 Hz, 1H), 4.23 (d, J=6.0 Hz, 2H), 4.00 (q,J=6.9 Hz, 1H), 2.94 (s, 3H), 2.13 (s, 3H), 1.82 (d, J=7.1 Hz, 3H), 1.19(d, J=6.8 Hz, 3H). ESMS (M+1)=461.48.

Diastereomer B: Chiral HPLC(Chiral PAK IC column, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine): Rt=7.17 mins.; 99%ee. 1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.62 (s, 1H), 7.86 (d,J=1.5 Hz, 2H), 7.80 (d, J=0.9 Hz, 1H), 7.45 (d, J=0.8 Hz, 1H), 6.68(brs, 1H), 5.78 (q, J=7.1 Hz, 1H), 4.25 (d, J=5.9 Hz, 2H), 4.02 (q,J=6.8 Hz, 1H), 2.95 (s, 3H), 2.14 (s, 3H), 1.82 (d, J=7.1 Hz, 3H), 1.21(d, J=6.8 Hz, 3H). ESMS (M+1)=461.48.

Compound 176:(7S)-5-((4-(((4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)picolinonitrile

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-56 to provide the title compound; 15% yield. 1HNMR (300 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.59 (d, J=2.1 Hz, 1H), 8.00 (d,J=8.0 Hz, 1H), 7.83-7.70 (m, 2H), 7.42 (s, 1H), 6.56 (t, J=6.0 Hz, 1H),5.44 (s, 2H), 4.22 (dd, J=6.2, 1.5 Hz, 2H), 3.99 (q, J=6.8 Hz, 1H), 2.93(s, 3H), 2.13 (s, 3H), 1.18 (d, J=6.8 Hz, 3H). ESMS (M+1)=404.3.

Compound 178:(7S)-4,7,8-trimethyl-2-(((1-((2-methylpyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediate A-2 and(1-((2-methylpyridin-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride to provide the title compound; 43% yield. 1H NMR (400 MHz,Methanol-d4) δ 8.62 (d, J=6.2 Hz, 1H), 7.89 (s, 1H), 7.66 (s, 1H), 7.58(s, 1H), 7.49 (d, J=6.2 Hz, 1H), 5.65 (s, 2H), 4.57 (s, 2H), 4.30 (q,J=6.9 Hz, 1H), 3.27 (s, 3H), 2.75 (s, 3H), 2.31 (s, 3H), 1.53 (d, J=6.9Hz, 3H); ESMS (M+1)=393.30.

Compound 180:(7S)-2-(((1-((2-fluoropyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-58 to provide the title compound; 14% yield. 1HNMR (300 MHz, CDCl₃) δ 8.16 (d, J=5.2 Hz, 1H), 7.57 (d, J=9.3 Hz, 2H),7.03-6.92 (m, 1H), 6.64 (s, 1H), 5.33 (s, 2H), 4.49 (s, 2H), 4.15 (q,J=6.9 Hz, 1H), 3.17 (s, 3H), 2.30 (s, 3H), 1.50 (d, J=6.9 Hz, 3H); ESMS(M+1)=397.26.

Compound 182:(7S)-4,7,8-trimethyl-2-(((1-((4-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-59 to provide the title compound; 51% yield. 1HNMR (300 MHz, CDCl₃) δ 8.79-8.70 (m, 1H), 8.34-8.27 (m, 1H), 7.62-7.52(m, 2H), 7.49 (s, 1H), 5.52 (s, 2H), 4.48 (d, J=5.8 Hz, 2H), 4.13 (q,J=6.9 Hz, 1H), 3.12 (s, 3H), 2.30 (s, 3H), 1.47 (d, J=6.9 Hz, 3H). ESMS(M+1)=447.18.

Compound 183:(7S))-4,7,8-trimethyl-2-(((1-((2-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-60 to provide the title compound; 56% yield. 1HNMR (300 MHz, CDCl₃) δ 8.64 (d, J=4.2 Hz, 1H), 7.62-7.44 (m, 3H), 7.38(d, J=7.7 Hz, 1H), 5.53 (s, 2H), 4.51 (d, J=5.7 Hz, 2H), 4.20 (q, J=6.9Hz, 1H), 3.20 (s, 3H), 2.38 (s, 3H), 1.56 (d, J=6.9 Hz, 3H); ESMS(M+1)=447.15.

Compound 184:(7S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-61 to provide the title compound; 41% yield. 1HNMR (400 MHz, Methanol-d4) δ 7.95 (t, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.70(d, J=7.8 Hz, 1H), 7.54 (s, 1H), 7.20 (d, J=7.9 Hz, 1H), 5.48 (s, 2H),4.43 (s, 2H), 4.09 (q, J=6.9 Hz, 1H), 3.08 (s, 3H), 2.19 (s, 3H), 1.35(d, J=6.9 Hz, 3H); ESMS (M+1)=447.28.

Compound 187:(7S)-4,7,8-trimethyl-2-(((1-((3-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-62 to provide the title compound; 48% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.65 (d, J=5.3 Hz, 1H), 7.75(s, 1H), 7.61 (s, 1H), 6.66 (d, J=5.3 Hz, 1H), 5.61 (s, 2H), 4.45 (s,2H), 4.09 (q, J=6.8 Hz, 1H), 3.08 (s, 3H), 2.19 (s, 3H), 1.34 (d, J=6.9Hz, 3H); ESMS (M+1)=447.32. Chiral HPLC (Chiralpak AD-H; 50% (1:1MeOH-EtOH)/50% Heptane (0.2% diethylamine): 70% ee.

Compound 188:(S)-4,7,8-trimethyl-2-(((1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-63 to provide the title compound; 17% yield. 1HNMR (300 MHz, CDCl₃) δ 9.47 (s, 1H), 7.55 (d, J=0.7 Hz, 1H), 7.45 (d,J=7.9 Hz, 1H), 7.39-7.32 (m, 1H), 7.22 (d, J=7.9 Hz, 1H), 5.31 (s, 2H),5.11 (t, J=5.9 Hz, 1H), 4.57-4.29 (m, 2H), 4.03 (q, J=6.8 Hz, 1H), 3.01(s, 3H), 2.57 (s, 3H), 2.24 (s, 3H), 1.37 (d, J=6.8 Hz, 3H). ESMS(M+1)=461.43. Chiral HPLC(Chiral PAK IC column, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine): Rt=7.998 mins., (97%ee).

Compound 194:(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneStep 1: MethylN-(2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate

A mixture of intermediates A-40 (MethylN-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate; 400mg, 1.39 mmol) and intermediate B-67((1-((6-Chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride; 482 mg, 1.45 mmol) were taken intoN-methylpyrrolidin-2-one (5 ml) and triethylamine (1 ml, 7 mmol) andheated at 60° C. for 2 hours. The reaction was cooled to roomtemperature and poured onto ice resulting in a yellow precipitate. Theprecipitate was collected by vacuum filtration then purified by columnchromatography (SiO₂) eluting with a gradient of 0-8% methanol indichloromethane. The desired fractions were evaporated in vacuo toprovide the title product, wt. 312 mg (46.8% yield). 1H NMR (300 MHz,CDCl₃) δ 8.32 (d, J=2.5 Hz, 1H), 7.59-7.45 (m, 2H), 7.38 (s, 1H), 7.32(d, J=8.2 Hz, 1H), 5.49 (s, 1H), 5.27 (s, 2H), 4.92 (d, J=7.4 Hz, 1H),4.40 (dt, J=14.2, 8.4 Hz, 2H), 3.65 (s, 3H), 2.87 (s, 3H), 2.42 (s, 3H),1.53 (d, J=7.4 Hz, 3H); ESMS (M+1)=475.35.

Step 2:(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

Platinum on carbon (30 mg) was added to a solution of methylN-(2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate(150 mg, 0.31 mmol) in tetrahydrofuran (5 ml) and placed under hydrogenat 50 psi for 16 hours. The reaction was filtered through Celite andFlorisil and rinsed well with dichloromethane. The solvent wasevaporated in vacuo and the crude product purified column chromatographyeluting with a gradient of 0-10% methanol in dichloromethane. Thedesired fractions were evaporated to provide the title product, 47 mg(35% yield). 1H NMR (300 MHz, CDCl₃) δ 9.21 (s, 1H), 8.27 (dd, J=2.5,0.8 Hz, 1H), 7.52 (d, J=0.7 Hz, 1H), 7.50-7.43 (m, 1H), 7.38 (d, J=0.8Hz, 1H), 7.31-7.24 (m, 1H), 5.24 (s, 2H), 5.00 (t, J=5.8 Hz, 1H), 4.41(dd, J=5.8, 1.6 Hz, 2H), 4.05 (q, J=6.8 Hz, 1H), 3.02 (s, 3H), 2.24 (s,3H), 1.38 (d, J=6.8 Hz, 3H). ESMS (M+1)=413.46. Chiral HPLC (ChiralPAKIC column; 20% methanol/30% ethanol/50% hexane): Rt 15.484 minutes; (95%ee).

Compound 195:(7S)-7,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-1 and B-52 to provide the title compound; 15% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.83-7.74 (m, 1H), 7.72 (s,1H), 7.53 (s, 1H), 7.37 (s, 1H), 5.45 (s, 1H), 4.38 (s, 1H), 4.10 (q,J=6.9 Hz, 1H), 3.05 (s, 1H), 1.38 (d, J=6.9 Hz, 1H). ESMS (M+1)=433.28.Chiral HPLC(Chiral PAK IC column, 4.6×250 mm; 50% hexane/30% ethanol/20%methanol/0.1% diethylamine): Rt 16.928 mins. (97.8% ee).

Compound 196:(7S)-2-(((1-((6-(dimethylamino)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(200 mg, 0.4972 mmol) and N,N-dimethylamine (75.55 μL, 0.5966 mmol) weretaken into methanol and heated at 70° C. in a sealed tube for 16 hours.The reaction evaporated in vacuo and the crude purified by columnchromatography (SiO₂) eluting with gradient of 0-20% methanol indichloromethane. The desired fractions were combined and evaporated toafford the title compound, wt. 144 mg (67% yield). 1H NMR (300 MHz,DMSO-d6) δ 10.05 (s, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.61 (s, 1H), 7.42(dd, J=8.7, 2.5 Hz, 1H), 7.35 (s, 1H), 7.05 (brs, 1H), 6.58 (d, J=8.8Hz, 1H), 5.09 (s, 2H), 4.24 (d, J=5.9 Hz, 2H), 4.09 (q, J=6.9 Hz, 1H),2.98 (s, 9H), 2.16 (s, 3H), 1.25 (d, J=6.9 Hz, 3H). ESMS (M+1)=422.4.

Compound 197:(7S)-2-(((1-((6-methoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-64 to provide the title compound; 40% yield. 1HNMR (300 MHz, CDCl₃) δ 8.46 (s, 1H), 8.09 (dd, J=2.5, 0.8 Hz, 1H), 7.51(d, J=0.8 Hz, 1H), 7.47 (dd, J=8.6, 2.5 Hz, 1H), 7.34 (d, J=0.8 Hz, 1H),6.73 (dd, J=8.6, 0.7 Hz, 1H), 5.19 (s, 2H), 4.98 (s, 1H), 4.41 (d, J=5.7Hz, 2H), 3.94 (s, 3H), 3.04 (s, 3H), 2.23 (s, 3H), 1.40 (d, J=6.8 Hz,3H). ESMS (M+1)=409.34.

Compound 198:(7S)-4,7,8-trimethyl-2-(((1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

MethylN-(2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-alaninate(See compound 194, step 1; 75 mg, 0.13 mmol) and 10% palladium/carbon(13 mg) was taken in methanol (5 ml) and hydrogenated under hydrogen at50 psi for 16 hours. The reaction was filtered through Celite and thefiltrate evaporated in vacuo. The crude product was purified by reversephase chromatography (C18) to provide the title product, wt 16 mg (33%yield). 1H NMR (300 MHz, Methanol-d4) δ 8.81-8.67 (m, 1H), 8.65 (s, 1H),8.30 (d, J=8.2 Hz, 1H), 7.94 (t, J=7.1 Hz, 1H), 7.80 (s, 1H), 7.61-7.44(m, 1H), 5.49 (d, J=4.3 Hz, 2H), 4.45 (s, 2H), 4.30-4.09 (m, 1H),3.20-3.05 (m, 3H), 2.30-2.04 (m, 3H), 1.54-1.32 (m, 3H); ESMS(M+1)=379.39.

Compound 199:(7S)-4,7,8-trimethyl-2-(((1-((5-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-66 to provide the title compound; 69% yield. 1HNMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.46-8.36 (m, 1H), 7.74 (s, 1H),7.73-7.68 (m, 1H), 7.41 (d, J=0.8 Hz, 1H), 6.61 (t, J=6.0 Hz, 1H), 5.39(s, 2H), 4.22 (dd, J=6.1, 1.9 Hz, 2H), 4.01 (dd, J=11.0, 7.0 Hz, 1H),2.93 (s, 3H), 2.41 (d, J=2.2 Hz, 3H), 2.13 (s, 3H), 1.18 (d, J=6.8 Hz,3H). ESMS (M+1)=461.39.

Compound 185:(7S)-2-(((1-((2-chloropyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general method B via reaction ofintermediate A-2 and[1-[(2-chloro-4-pyridyl)methyl]pyrazol-4-yl]methanamine hydrochloride toprovide the title compound; 58% yield. 1H NMR (400 MHz, Methanol-d4) δ8.30 (d, J=5.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H),7.13 (d, J=5.2 Hz, 1H), 7.11 (s, 1H), 5.40 (s, 2H), 4.54 (s, 2H), 4.29(t, J=6.9 Hz, 1H), 3.25 (d, J=3.6 Hz, 3H), 2.29 (s, 3H), 1.51 (dd,J=14.4, 7.2 Hz, 3H). ESMS (M+1)=413.25.

Compound 200:(7S)-4,7,8-trimethyl-2-(((1-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-68 to provide the title compound; 27% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.82 (s, 1H), 8.05 (dd, J=8.3, 2.1 Hz, 1H),7.74 (s, 1H), 7.54 (s, 1H), 7.15 (d, J=8.2 Hz, 1H), 5.50 (s, 2H), 4.42(s, 2H), 4.07 (q, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.18 (s, 3H), 1.32 (d,J=6.8 Hz, 3H). ESMS (M+1)=447.28.

Compound 201:(7S)-4,7,8-trimethyl-2-(((1-((4-(trifluoromethyl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-69 to provide the title compound; 11% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.76 (d, J=5.1 Hz, 1H), 7.84 (s, 1H),7.64-7.55 (m, 2H), 7.32 (s, 1H), 5.52 (s, 2H), 4.54 (s, 2H), 4.30 (q,J=6.9 Hz, 1H), 3.25 (s, 2H), 2.28 (s, 2H), 1.52 (d, J=6.9 Hz, 2H). ESMS(M+1)=447.28.

Compound 12:(7S)-2-(((1-((2-(dimethylamino)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general method B via reaction of A-2 and4-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-N,N-dimethylpyridin-2-aminedihydrochloride to provide the title compound; 46% yield. 1H NMR (400MHz, Methanol-d4) δ 7.85 (d, J=6.0 Hz, 1H), 7.83 (d, J=6.7 Hz, 1H), 7.63(s, 1H), 6.92 (s, 1H), 6.61 (dd, J=6.7, 1.4 Hz, 1H), 5.45 (s, 2H), 4.55(s, 2H), 4.30 (q, J=6.9 Hz, 1H), 3.26 (d, J=6.3 Hz, 3H), 3.25 (s, 6H),2.30 (s, 3H), 1.53 (d, J=6.9 Hz, 3H). ESMS (M+1)=422.39.

Compound 202:(7S)-2-(((1-((2-hydroxypyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general method by via reaction ofintermediates A-2 and(1-((2-methoxy-4-pyridyl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride. Under the conditions of the reaction, the methoxy groupwas lost to provide the title compound; 52% yield. 1H NMR (400 MHz,Methanol-d4) δ 7.79 (s, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.42 (d, J=6.8 Hz,1H), 6.26 (dd, J=6.8, 1.4 Hz, 1H), 6.07 (s, 1H), 5.25 (d, J=10.6 Hz,2H), 4.53 (s, 2H), 4.30 (p, J=7.0 Hz, 1H), 3.26-3.22 (m, 3H), 2.29 (s,3H), 1.58-1.49 (m, 3H); ESMS (M+1)=395.35.

Compound 203:(7S)-2-(((1-((2-methoxypyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general method A via reaction of A-2 and(1-((2-methoxypyridin-4-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride to provide the title compound; 21% yield. 1H NMR (400 MHz,CDCl₃) δ 8.55 (s, 1H), 8.02 (d, J=5.3 Hz, 1H), 7.46 (s, 1H), 7.31 (s,1H), 6.55 (d, J=5.3 Hz, 1H), 6.36 (s, 1H), 5.14 (s, 2H), 4.83 (t, J=5.4Hz, 1H), 4.34 (t, J=7.6 Hz, 2H), 3.98 (q, J=6.9 Hz, 1H), 3.83 (s, 3H),2.96 (s, 3H), 2.16 (s, 3H), 1.31 (t, J=7.1 Hz, 3H). ESMS (M+1)=409.28.

Compound 204:(7S)-4-((4-(((4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)picolinonitrile

The compound was prepared by general method B via reaction of A-2 and4-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)picolinonitrile hydrochlorideto provide the title compound; 34% yield. 1H NMR (400 MHz, Methanol-d4)δ 8.63 (d, J=5.1 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.40(d, J=4.8 Hz, 1H), 5.46 (s, 2H), 4.56 (d, J=15.7 Hz, 2H), 4.30 (q, J=6.9Hz, 1H), 3.25 (s, 3H), 2.29 (s, 3H), 1.53 (d, J=6.9 Hz, 3H). ESMS(M+1)=404.17.

Compound 206:(7S)-4,7,8-trimethyl-2-(((1-((5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-70 to provide the title compound; 21% yield. 1HNMR (300 MHz, CDCl₃) δ 8.85 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 7.85 (s,1H), 7.76 (t, J=2.2 Hz, 1H), 7.63-7.50 (m, 1H), 7.45 (d, J=0.8 Hz, 1H),5.37 (s, 2H), 5.03 (s, 1H), 4.45 (dd, J=5.8, 1.8 Hz, 2H), 4.09 (q, J=6.9Hz, 1H), 3.06 (s, 4H), 2.23 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). ESMS(M+1)=447.43.

Compound 207:(7S)-4,7,8-trimethyl-2-(((1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-71 to provide the title compound; 49% yield. 1HNMR (400 MHz, Methanol-d4) δ 8.62 (d, J=5.0 Hz, 1H), 7.75 (s, 1H), 7.58(s, 1H), 7.50 (s, 1H), 7.33 (d, J=4.9 Hz, 1H), 5.47 (s, 2H), 4.44 (s,2H), 4.09 (q, J=6.9 Hz, 1H), 3.07 (s, 3H), 2.19 (s, 3H), 1.34 (d, J=6.9Hz, 3H). ESMS=447.28. Chiral HPLC (Chiralpak AD-H; 50%(Methanol:ethanol/50% Heptane): 99.3% ee.

Compound 210:(7S)-2-(((1-((4-methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-72 to provide the title compound; 22% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.08 (s, 1H), 7.67 (s, 1H), 7.47 (d, J=15.8Hz, 2H), 5.49 (s, 1H), 5.36 (s, 2H), 4.39 (s, 2H), 4.00 (s, 3H), 3.05(s, 3H), 2.18 (s, 3H), 1.32 (d, J=6.6 Hz, 3H). ESMS (M+1)=477.42. ChiralHPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1%diethylamine). Rt=8.40 mins.; 97.5% ee.

Compound 211:(7S)-2-(((1-((6-(tert-butyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-73 to provide the title compound; 89% yield. 1HNMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.40 (d, J=2.3 Hz, 1H), 7.77-7.65(s, 1H), 7.54 (dd, J=8.2, 2.4 Hz, 1H), 7.37 (td, J=4.1, 3.6, 0.9 Hz,2H), 6.58 (t, J=6.0 Hz, 1H), 5.25 (s, 2H), 4.21 (s, 1H), 3.99 (q, J=6.8Hz, 1H), 2.93 (s, 3H), 2.12 (s, 3H), 1.27 (s, 9H), 1.18 (d, J=6.8 Hz,3H). ESMS (M+1)=435.45. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine). Rt=8.59 mins.; 97.9%ee.

Compound 209:(7S)-2-(((1-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-74 to provide the title compound; 29% yield. 1HNMR (300 MHz, CDCl₃) δ 9.14 (s, 1H), 8.28 (s, 1H), 7.49 (s, 1H),7.31-7.04 (m, 1H), 5.26 (d, J=21.4 Hz, 2H), 4.95 (t, J=5.8 Hz, 1H), 4.36(dd, J=5.6, 2.3 Hz, 2H), 3.98 (q, J=6.8 Hz, 1H), 2.95 (s, 3H), 2.17 (s,3H), 1.31 (d, J=6.8 Hz, 3H); ESMS (M+1)=465.35. Chiral HPLC (ChiralpakIC, 4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1% diethylamine).Rt=5.59 mins.; 95% ee.

Compound 218:(7S)-2-(((1-((2-methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-75 to provide the title compound; 18% yield. 1HNMR (300 MHz, Methanol-d4) δ 7.70 (s, 1H), 7.55 (s, 1H), 7.33 (s, 2H),5.35 (s, 2H), 4.43 (s, 2H), 4.24-3.90 (m, 4H), 3.08 (s, 3H), 2.21 (s,3H), 1.35 (d, J=6.6 Hz, 3H). ESMS (M+1)=477.33. Chiral HPLC (ChiralpakIC, 4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1% diethylamine).Rt=5.59 mins.; 95.9% ee.

Compound 215:(7S)-2-(((1-((6-methoxy-5-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-76 to provide the title compound; 78% yield. 1HNMR (300 MHz, CDCl₃) δ 8.28-8.18 (m, 1H), 7.81-7.73 (m, 1H), 7.69 (s,1H), 7.54 (d, J=0.7 Hz, 1H), 7.39 (d, J=0.8 Hz, 1H), 5.24 (s, 2H), 4.89(s, 1H), 4.48-4.35 (m, 2H), 4.10 (t, J=6.9 Hz, 1H), 4.05 (s, 3H), 3.05(s, 3H), 2.22 (s, 3H), 1.41 (d, J=6.9 Hz, 3H). ESMS (M+1)=477.37.

Compound 213:(7S)-2-(((1-((5-methoxy-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-77 to provide the title compound; 44% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.12-7.97 (m, 1H), 7.80 (d, J=2.6 Hz, 1H),7.62 (d, J=2.6 Hz, 1H), 7.55 (s, 1H), 5.60-5.33 (m, 2H), 4.58-4.31 (m,2H), 4.15 (tdd, J=6.8, 6.3, 5.6, 2.2 Hz, 1H), 4.06-3.77 (m, 3H), 3.12(dt, J=3.6, 1.7 Hz, 3H), 2.26 (dd, J=2.5, 1.1 Hz, 3H), 1.51-1.19 (m,3H); ESMS (M+1)=477.28. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine). Rt=5.59 mins.; 92%ee.

Compound 208:(7S)-2-(((1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-2 and B-78 to provide the title compound; 12% yield. 1HNMR (300 MHz, CDCl₃) δ 8.35 (d, J=2.7 Hz, 1H), 8.26 (d, J=1.7 Hz, 1H),7.48 (d, J=0.7 Hz, 1H), 7.33 (d, J=0.8 Hz, 1H), 7.13 (ddt, J=8.9, 2.6,1.2 Hz, 1H), 5.23 (d, J=0.9 Hz, 3H), 4.84 (t, J=5.8 Hz, 1H), 4.41-4.29(m, 2H), 3.99 (q, J=6.8 Hz, 1H), 2.96 (s, 3H), 2.15 (s, 3H), 1.32 (d,J=6.9 Hz, 3H); ESMS (M+1)=397.32.

Compound 205:(7S)-2-(((1-((6-fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-3 and B-79 to provide the title compound; 16% yield. 1HNMR (300 MHz, CDCl₃) δ 7.96 (s, 1H), 7.53 (d, J=0.7 Hz, 1H), 7.28 (d,J=1.7 Hz, 2H), 6.79 (dt, J=2.3, 0.7 Hz, 1H), 5.27 (s, 2H), 4.90 (t,J=5.8 Hz, 1H), 4.01 (q, J=6.9 Hz, 1H), 3.30 (s, 3H), 3.00 (s, 3H), 2.35(s, 3H), 2.30 (d, J=0.8 Hz, 3H), 1.92 (s, 1H), 1.20 (d, J=6.9 Hz, 3H);ESMS (M+1)=425.41. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30%ethanol/20% methanol/0.1% diethylamine). Rt=5.59 mins.; 80% ee.

Compound 385:(7S)-8-isopropyl-4,7-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-4 and B-52 to provide the title compound; 69% yield. 1HNMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 10.49 (s, 1H), 8.64 (s, 1H),7.99 (s, 1H), 7.94-7.77 (m, 3H), 7.49 (s, 1H), 5.49 (s, 2H), 4.61-4.38(m, 3H), 4.31 (q, J=6.8 Hz, 1H), 2.29 (s, 3H), 1.46-1.15 (m, 9H); ESMS(M+1)=475.24. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30%ethanol/20% methanol/0.1% diethylamine). Rt=6.045 mins.; 95.7% ee.

Compound 220:(7S)-4,8-dimethyl-7-propyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-7 and B-52 to provide the title product as a mixture ofenantiomers that were separated by SFC (Column AD-H, 10×250 mm; 30%Ethanol (0.2% diethylamine)/70% CO2, isocratic) to provide the titleproduct (Peak A: Rt=0.739 mins.; 99.6% ee). 1H NMR (300 MHz, DMSO-d6) δ9.87 (s, 1H), 8.71-8.54 (m, 1H), 7.87 (td, J=8.1, 1.5 Hz, 2H), 7.76 (s,1H), 7.42 (s, 1H), 6.59 (t, J=5.9 Hz, 1H), 5.45 (s, 2H), 4.22 (d, J=6.0Hz, 2H), 4.00 (dd, J=6.8, 4.0 Hz, 1H), 2.96 (s, 3H), 2.11 (s, 3H),1.81-1.48 (m, 2H), 1.29-1.10 (m, 2H), 0.83 (t, J=7.3 Hz, 3H). ESMS(M+1)=475.3.

Compound 383:(7S)-7-isopropyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-9 and B-52 to provide the title compound; 66% yield. 1HNMR (300 MHz, CDCl₃) δ 8.60 (s, 1H), 8.54 (bs, 1H), 7.57 (s, 1H), 7.50(s, 1H), 5.38 (s, 2H), 4.49 (d, J=5.6 Hz, 2H), 3.95 (d, J=4.2 Hz, 1H),3.17 (s, 3H), 2.28 (s, 4H), 1.10 (d, J=7.0 Hz, 3H), 0.93 (d, J=7.0 Hz,3H). ESMS (M+1)=475.25. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine). Rt=6.125 mins.; (95%ee).

Compound 384:(7S)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-9 and B-53 to provide the title compound; 16% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.14-8.04 (m, 1H), 7.92-7.77 (m, 2H), 7.62(d, J=0.7 Hz, 1H), 7.09-6.99 (m, 1H), 5.38 (s, 2H), 4.52 (s, 2H), 4.14(d, J=3.8 Hz, 1H), 3.24 (s, 3H), 2.36-2.29 (m, 2H), 2.27 (s, 3H), 1.09(d, J=7.0 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H). ESMS (M+1)=425.32. ChiralHPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1%diethylamine). Rt=9.887 mins. (98.4% ee); [α]_(D)=89.1° (c=1, methanol).

Compound 400:(7S)-4,7-dimethyl-8-(methyl-d3)-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-38 and B-52 to provide the title compound; 84% yield. 1HNMR (300 MHz, CDCl₃) δ 8.83 (s, 1H), 8.51 (d, J=1.7 Hz, 1H), 7.68-7.53(m, 2H), 7.53-7.41 (m, 1H), 7.42-7.29 (m, 1H), 5.29 (s, 2H), 4.44-4.24(m, 2H), 3.99 (q, J=6.9 Hz, 1H), 2.17 (s, 3H), 1.32 (d, J=6.9 Hz, 3H).ESMS (M+1)=450.26. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 20%methanol/30% ethanol/50% hexane (0.1% diethylamine); Rt 7.88 mins. (97%ee).

Compound 386:(7S)-7-Cyclopropyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure method A via reaction ofA6 and B-52 to provide the title compound; 46% yield. 1H NMR (300 MHz,DMSO-d6) δ 9.86 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 7.87 (td, J=7.8, 1.5Hz, 2H), 7.77 (s, 1H), 7.44 (d, J=0.7 Hz, 1H), 6.64 (t, J=6.0 Hz, 1H),5.45 (s, 2H), 4.24 (dd, J=6.0, 3.1 Hz, 2H), 3.31 (d, J=8.9 Hz, 1H), 3.02(s, 3H), 2.14 (s, 3H), 0.95-0.72 (m, 1H), 0.60-0.26 (m, 4H); ESMS(M+1)=473.32.

Compound 387:(7S)-4,7,8-Trimethyl-2-(((1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure method A via reaction ofA-2 and B-81 to provide the title compound; 71% yield. 1H NMR (300 MHz,DMSO-d6) δ 9.80 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.68 (d, J=0.8 Hz, 1H),7.49 (d, J=8.1 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 6.56 (t, J=6.1 Hz, 1H),5.48 (d, J=7.6 Hz, 2H), 5.46 (s, 1H), 5.16 (s, 1H), 4.24 (dd, J=6.0, 2.4Hz, 2H), 3.99 (q, J=6.8 Hz, 1H), 2.94 (s, 3H), 2.13 (s, 3H), 2.05 (t,J=1.2 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H). ESMS (M+1)=487.23.

Compound 388:(7S)-2-(((1-((2-isopropyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

To a solution(7S)-4,7,8-trimethyl-2-(((1-((2-(prop-1-en-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(220 mg, 0.44 mmol) in 20 ml of methanol was added 10% Pd/C (100 mg).The reaction was placed under an atmosphere of hydrogen (1 atm) andstirred at room temperature for 18 hours. The reaction was filteredthrough Celite and the filtrate evaporated in vacuo. The crude productwas purified by column chromatography eluting with a gradient of 0-20%methanol in dichloromethane. The desired fractions were evaporated toafford the product, wt. 204 mg (90% yield). 1H NMR (300 MHz, DMSO-d6) δ9.80 (s, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.65 (s, 1H), 7.49 (d, J=8.0 Hz,1H), 7.42 (d, J=0.8 Hz, 1H), 6.56 (t, J=6.1 Hz, 1H), 5.49 (s, 2H), 4.23(dd, J=6.1, 2.6 Hz, 2H), 3.99 (q, J=6.8 Hz, 1H), 3.40 (h, J=6.7 Hz, 1H),2.92 (s, 3H), 2.12 (s, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6 Hz,6H). ESMS (M+1)=489.25.

Compound 238:4,7,7,8-Tetramethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method B via reaction ofintermediates A-11 and B-52 to provide the title compound; 12.6% yield.1H NMR (300 MHz, CDCl₃) δ 8.60 (s, 1H), 7.68 (t, J=1.5 Hz, 2H),7.60-7.53 (m, 2H), 7.46 (s, 1H), 5.38 (s, 2H), 4.46 (d, J=5.8 Hz, 2H),3.09 (s, 3H), 2.25 (s, 3H), 1.54 (s, 6H); ESMS (M+1)=461.32.

Compound 237:5,7,7,8-Tetramethyl-2-(((1-((2-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-14 and B-61 to provide the title compound; 25% yield. 1HNMR (300 MHz, CDCl₃) δ 8.79-8.71 (m, 1H), 8.31 (d, J=1.0 Hz, 1H),7.63-7.48 (m, 3H), 7.37 (s, 1H), 5.52 (s, 2H), 4.50 (d, J=5.8 Hz, 2H),3.28 (s, 3H), 3.16 (s, 3H), 1.60 (s, 6H). ESMS (M+1)=461.18.

Compound 236:5,7,7,8-Tetramethyl-2-(((1-((4-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-14 and B-59 to provide the title compound; 35% yield. 1HNMR (300 MHz, CDCl₃) δ 8.64 (d, J=4.3 Hz, 1H), 7.62-7.44 (m, 3H), 7.38(d, J=7.8 Hz, 1H), 7.23 (s, 1H), 5.54 (s, 2H), 4.53 (d, J=5.7 Hz, 2H),3.25 (d, J=12.2 Hz, 6H), 1.66 (d, J=0.9 Hz, 6H). ESMS (M+1)=461.18.

Compound 186:(7S)-7-ethyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-8 and B-52 to provide the title compound; 80% yield. 1HNMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.63 (s, 1H), 7.85 (q, J=8.1 Hz,2H), 7.75 (s, 1H), 7.42 (s, 1H), 6.55 (t, J=6.2 Hz, 1H), 5.45 (s, 2H),4.22 (d, J=6.0 Hz, 2H), 3.99 (dd, J=6.4, 3.6 Hz, 1H), 2.96 (s, 3H), 2.11(s, 3H), 1.72 (m, 2H), 0.74 (t, J=7.4 Hz, 3H). ESMS (M+1)=461.48. ChiralHPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1%diethylamine). Rt=7.095 mins.; 95.1% ee.

Compound 392:(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, Methanol-d4) δ 7.60 (s, 1H), 7.48 (s, 1H), 7.22 (dd,J=8.5, 5.4 Hz, 2H), 7.03 (t, J=8.8 Hz, 2H), 5.25 (s, 2H), 4.39 (s, 2H),4.03 (q, J=6.9 Hz, 1H), 3.27 (s, 3H), 3.00 (s, 3H), 2.32 (s, 3H), 1.15(d, J=6.9 Hz, 3H); F19 NMR δ 118.04 ppm; ESMS (M+1)=410.36 mins. ChiralHPLC (IA column; 40% ethanol/60% hexane, isocratic), Rt=12.775 mins.(98% ee) [a,]_(D)=20.2° (c=1, methanol).

Compound 390:(7S)-4,7,8-trimethyl-2-(((1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-83 to provide the title compound; 88% yield. 1HNMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.74-7.62(m, 2H), 7.37 (s, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.60 (t, J=6.0 Hz, 1H),5.24 (s, 2H), 4.97 (q, J=9.1 Hz, 2H), 4.21 (d, J=6.0 Hz, 2H), 3.99 (q,J=6.7 Hz, 1H), 3.17 (d, J=4.9 Hz, 1H), 2.93 (s, 3H), 2.13 (s, 3H), 1.18(d, J=6.7 Hz, 3H). ESMS (M+1)=477.28. Chiral HPLC (Chiralpak IC, 4.6×250mm; 50% hexane/30% ethanol/20% methanol/0.1% diethylamine). Rt=6.773mins.; 95.1% ee.

Compound 394:(7S)-7-Ethyl-2-(((1-((6-fluoro-5-methoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-8 and B-84 to provide the title compound; 59% yield. 1HNMR (300 MHz, CDCl₃) δ 7.55 (s, 2H), 7.45 (s, 1H), 7.33 (s, 1H), 7.10(d, J=9.6 Hz, 1H), 5.25 (d, J=16.2 Hz, 2H), 5.15 (s, 2H), 4.34 (d, J=5.6Hz, 2H), 3.99 (dd, J=6.4, 3.6 Hz, 1H), 3.76 (s, 3H), 2.98 (s, 3H), 2.16(s, 3H), 2.01-1.66 (m, 1H), 0.81 (t, J=7.4 Hz, 3H). ESMS (M+1)=441.3.Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30% ethanol/20%methanol/0.1% diethylamine). Rt=11.614 mins.; 96.7% ee.

Compound 391:(S)-7-cyclopropyl-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-6 and B-53 to provide the title compound; 1H NMR (300MHz, CDCl₃) δ 8.84 (s, 1H), 8.11 (dt, J=2.6, 0.9 Hz, 1H), 7.65 (ddd,J=8.3, 7.6, 2.6 Hz, 1H), 7.53 (d, J=0.7 Hz, 1H), 7.46-7.35 (m, 1H),6.98-6.84 (m, 1H), 5.49 (s, 1H), 5.26 (s, 2H), 4.44 (dd, J=5.6, 1.7 Hz,2H), 3.29 (d, J=9.1 Hz, 1H), 3.14 (s, 3H), 2.26 (s, 3H), 1.38-1.13 (m,1H), 1.07-0.90 (m, 1H), 0.76-0.63 (m, 1H), 0.63-0.38 (m, 2H); ESMS(M+1)=423.34.

Compound 389:(7S)-7-Ethyl-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-8 and B-53 to provide the title compound; 13% yield. 1HNMR (300 MHz, CDCl₃) δ 8.99 (s, 1H), 8.04 (d, J=2.7 Hz, 1H), 7.65-7.50(m, 1H), 7.45 (s, 1H), 7.31 (s, 1H), 6.82 (dd, J=8.4, 2.9 Hz, 1H), 5.18(s, 2H), 4.92 (t, J=5.7 Hz, 1H), 4.34 (d, J=5.8 Hz, 2H), 3.97 (dd,J=6.4, 3.8 Hz, 1H), 2.97 (s, 3H), 2.15 (s, 3H), 1.98-1.79 (m, 1H),1.79-1.64 (m, 1H), 0.82 (t, J=7.5 Hz, 3H). ESMS (M+1)=411.31. ChiralHPLC (Chiralpak IC, 4.6×250 mm; 50% hexane/30% ethanol/20% methanol/0.1%diethylamine). Rt=11.481 mins.; 93.7% ee.

Compound 395:(7S)-8-Ethyl-4,7-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-44 and B-52 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 8.53 (s, 1H), 7.87-7.61 (m, 3H), 7.52 (s, 1H), 5.45(s, 2H), 4.40 (s, 2H), 4.22-3.85 (m, 3H), 2.17 (s, 3H), 1.42-0.98 (m,6H). ESMS (M+1)=461.52. Chiral HPLC (Chiralpak IC, 4.6×250 mm; 50%hexane/30% ethanol/20% methanol/0.1% diethylamine) Rt 6.831 mins.; 98%ee.

Compound 396:(7S)-7-Cyclopropyl-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-6 and B-89 to provide the title product. 1H NMR (300MHz, DMSO-d6) δ 9.82 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H), 6.59 (d, J=7.8Hz, 2H), 5.44 (s, 2H), 4.22 (dd, J=6.0, 3.3 Hz, 2H), 3.88 (s, 3H),3.39-3.26 (d, 1H), 3.02 (s, 3H), 2.14 (s, 3H), 1.01-0.73 (m, 1H),0.64-0.23 (m, 4H). ESMS (M+1)=476.55. Analytical SFC (AD-H column,4.6×100 mm; 40% isopropanol (5 mM ammonia)/60% CO₂, isocratic) Rt 1.061mins. (98% ee); [a,]_(D)=+54.7° (C=1, methanol).

Compound 397:(7S)-7-Isopropyl-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A by reaction ofintermediates A-9 and B-89 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.97 (s, 1H), 7.43 (s, 1H), 7.25 (s, 1H), 6.41 (s, 1H),5.23 (s, 2H), 4.88 (d, J=5.9 Hz, 1H), 4.33 (d, J=5.8 Hz, 2H), 3.79 (d,J=4.4 Hz, 1H), 3.77 (s, 3H), 3.01 (s, 3H), 2.14 (s, 4H), 0.98 (d, J=7.0Hz, 3H), 0.84 (d, J=6.9 Hz, 3H). ESMS (M+1)=478.57. Chiral HPLC(ChiralPAK IC column; 20% Methanol/30% ethanol/50% hexanes, isocratic)Rt 5.24 mins., 98% ee.

Compound 398:4′,8′-dimethyl-2′-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-17 and B-52 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.45 (s, 1H), 7.58 (t, J=7.0 Hz, 2H), 7.42 (d, J=10.9 Hz,2H), 5.27 (s, 2H), 4.31 (s, 2H), 3.14 (s, 3H), 2.75-2.27 (m, 4H), 2.08(s, 3H), 1.95 (q, J=9.3, 8.8 Hz, OH), 1.87-1.67 (m, 1H). ESMS(M+1)=473.27.

Compound 239:4′,8′-dimethyl-2′-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[cyclopropane-1,7′-pteridin]-6′-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-16 and B-52 to provide the title product, 53% yield. 1HNMR (300 MHz, Methanol-d4) δ 8.28 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.55(s, 1H), 7.16 (dd, J=13.5, 5.8 Hz, 2H), 5.55 (s, 2H), 4.64 (d, J=2.4 Hz,2H), 4.00 (dq, J=14.4, 7.2 Hz, 1H), 3.91-3.75 (m, 2H), 3.56 (dq, J=14.0,6.9 Hz, 1H), 2.20-1.91 (m, 3H), 1.70 (s, 3H), 1.21 (t, J=7.0 Hz, 6H),0.77 (t, J=7.3 Hz, 3H); ESMS (M+1)=459.41.

Compound 212:(7S)-2-(((3,5-Dimethyl-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofA-2 and B-82 to provide the title compound. 1H NMR (300 MHz, CDCl₃) δ8.52-8.45 (m, 1H), 7.73-7.54 (m, 2H), 5.31 (s, 2H), 4.31 (s, 2H), 4.06(q, J=6.8 Hz, 1H), 3.08 (d, J=1.1 Hz, 3H), 2.26 (s, 3H), 2.22 (d, J=5.1Hz, 6H), 1.39 (d, J=6.8 Hz, 3H). ESMS (M+1)=475.39.

Compound 216 and Compound 217:(7S)-4,7,8-Trimethyl-2-(((S)-1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-Trimethyl-2-(((R)-1-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)ethyl)amino)-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by general procedure Method A via reactionof A-2 and B-99 to provide a mixture of diastereomers (Compound 214).The pair diastereomers were separated by SFC (AD-H column, 10×250 mm;40% EtOH (0.2% diethylamine), 60% CO2):

Diastereomer A: SFC(Rt 0.627 mins.; 99.2% ee); 1H NMR (300 MHz, DMSO-d6)δ 9.81 (s, 1H), 8.62 (d, J=1.9 Hz, 1H), 7.95-7.79 (m, 2H), 7.75 (s, 1H),7.43 (s, 1H), 6.46 (d, J=8.7 Hz, 1H), 5.44 (s, 2H), 5.01 (q, J=7.3, 6.8Hz, 1H), 3.99 (q, J=6.7 Hz, 1H), 2.92 (s, 3H), 2.12 (s, 3H), 1.37 (d,J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H); ESMS (M+1)=461.34.

Diastereomer B: SFC (Rt 0.814 mins.; 99.4% ee); 1H NMR (300 MHz,DMSO-d6) δ 9.80 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 7.97-7.80 (m, 2H), 7.75(s, 1H), 7.42 (s, 1H), 6.46 (d, J=8.7 Hz, 1H), 5.44 (s, 2H), 5.17-4.91(m, 1H), 3.98 (q, J=6.8 Hz, 1H), 2.92 (s, 3H), 2.12 (s, 3H), 1.38 (d,J=6.9 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H); ESMS (M+1)=461.39.

Compound 403:(7S)-4,7,8-trimethyl-2-(methyl((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

A solution of (7S)-2-chloro-4,7,8-trimethyl-5,7-dihydropteridin-6-one(A-2; 696.2 mg, 3.010 mmol) andN-methyl-1-[1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazol-4-yl]methanamine(Trifluoroacetic Acid (2)) (B-154; 1.5 g, 3.010 mmol) in n-BuOH (10.44mL) was heated in microwave at 165° C. for 30 min. The crude reactionmixture was diluted with EtOAc, washed with saturated NaHCO₃ solution,dried over MgSO4, filtered, and evaporated in vacuo. The crude productwas purified by column chromatography (SiO₂) eluting with a gradient ofdichloromethane to 20% MeOH/DCM. The desired fractions were collectedand evaporated to afford the title product, wt. 624 mg, 52.2% yield) 1HNMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.63 (s, 1H), 8.06-7.72 (m, 3H),7.43 (s, 1H), 5.46 (s, 2H), 4.73-4.40 (m, 2H), 4.02 (q, J=6.7 Hz, 1H),2.97 (s, 6H), 2.17 (s, 3H), 1.20 (d, J=6.8 Hz, 3H). ESMS (M+1)=461.34;Chiral HPLC (ChiralPAK IC column; 20% Methanol/30% ethanol/50% hexanes,isocratic) Rt 5.410 mins. (87% ee).

2E. Preparation of Compounds of Table 8 Compound 246:(7S)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

(7S)-2-Chloro-4,7,8-trimethyl-5,7-dihydropteridin-6-one (A-2) (2.492 g,10.99 mmol), 3-(3,4,5-trifluorophenoxy) cyclobutanamine hydrochloride(B-101) (2.899 g, 11.43 mmol) and t-BuXPhos palladium(II) phenethylaminechloride (377.3 mg, 0.5495 mmol) were taken into tBuOH (40 mL) anddegassed by bubbling nitrogen. Sodium t-butoxide (19 mL of 2 M, 38mmol)) was added to the reaction and the reaction was stirred at roomtemperature for 2 hours under a nitrogen atmosphere. Water (100 ml) wasadded to the reaction and extracted with ethyl acetate (3×100 ml). Thecombined extracts were dried over sodium sulfate, filtered, andevaporated in vacuo to afford the crude product that was purified bycolumn chromatography (SiO2) eluting with a gradient of 0 to 20%Methanol in dichloromethane. The desired fractions were evaporated invacuo and converted to a hydrochloride salt. Wt. 3.9 g. 1H NMR (300 MHz,DMSO-d6) δ 9.84 (s, 1H), 6.93-6.81 (m, 2H), 6.79 (d, J=7.1 Hz, 1H), 4.83(s, 1H), 4.39 (dd, J=13.4, 6.7 Hz, 1H), 4.00 (q, J=6.8 Hz, 1H), 2.93 (s,3H), 2.43-2.27 (m, 4H), 2.12 (s, 3H), 1.18 (d, J=6.8 Hz, 3H); ESMS(M+1)=408.3. Chiral HPLC (IC column; 10% methanol/10% ethanol/80% hexane(0.1% diethylamine): Rt 10.023 mins., 96% ee. [α]=+57.2 (c=0.5,methanol).

TABLE 8 Synthetic Comp # L₂-Ring B M + 1 Method Comp 242

372.28 B Comp 246

408.34 A Comp 248

390.29 B Comp 262

420.22 B Comp 276

374.26 B Comp 287

420.22 A Comp 291

408.21 A Comp 292

408.42 A Comp 295

390.15 A Comp 315

423.17 A Comp 324

423.24 A Comp 326

438.28 A Comp 333

424.23 A Comp 335

423.24 A Comp 339

368.38 B Comp 340

422.53 B Comp 342

384.37 B Comp 344

402.3 B Comp 347

453.27 A Comp 350

402.23 B Comp 352

414.28 B Comp 354

402.26 B Comp 357

373.31 B Comp 359

456.31 B Comp 361

421.18 B Comp 370

402.36 B Comp 303

388.17 A Comp 317

438.2 A Comp 329

424.23 A

Compound 242: (7S)-2-((trans3-(4-fluorophenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-100 to provide the title product, 138 mg (59%yield). 1H NMR (300 MHz, Methanol-d4) δ 7.00 (t, J=8.7 Hz, 2H),6.90-6.73 (m, 2H), 4.87 (dd, J=10.4, 6.1 Hz, 1H), 4.68-4.50 (m, 1H),4.32 (q, J=6.8 Hz, 1H), 3.23 (s, 3H), 2.73-2.53 (m, 4H), 2.36 (s, 3H),1.54 (d, J=6.9 Hz, 3H).

Compound 246:(7S)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-101 to provide the title product, 22.2 g (90.7%yield); 1H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 6.85 (dd, J=10.0, 6.0Hz, 2H), 6.77 (d, J=6.9 Hz, 1H), 4.91-4.74 (m, 1H), 4.39 (dd, J=13.1,6.5 Hz, 1H), 4.00 (q, J=6.7 Hz, 1H), 2.93 (s, 3H), 2.47-2.23 (m, 4H),2.13 (s, 3H), 1.19 (d, J=6.8 Hz, 3H); ESMS=408.3 (M+1); 96% ee (Column:IC column; 10% MeOH-10% EtOH/80% Hexans-0.1% diethylamine)

Compound 248: (7S)-2-((trans3-(3,4-difluorophenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-102 to provide the title product, 65 mg (63%yield); 1H NMR (300 MHz, Methanol-d4) δ 7.17 (dd, J=19.5, 9.2 Hz, 1H),6.78 (ddd, J=12.3, 6.6, 2.9 Hz, 1H), 6.69-6.53 (m, 1H), 4.69-4.50 (m,1H), 4.32 (q, J=6.9 Hz, 1H), 3.24 (s, 3H), 2.76-2.51 (m, 4H), 2.35 (s,3H), 1.53 (t, J=9.2 Hz, 3H); ESMS (M+H)=390.29.

Compound 262:(7S)-2-((trans-3-((5-fluoropyridin-3-yl)oxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-103 to provide the title product, 91 mg (27.6%yield) 1H NMR (300 MHz, Methanol-d4) δ 8.68 (s, 1H), 8.57 (d, J=1.9 Hz,1H), 8.19 (d, J=9.8 Hz, 1H), 4.79-4.63 (m, 1H), 4.38-4.25 (m, 1H), 3.25(s, 3H), 2.78 (s, 4H), 2.37 (d, J=6.7 Hz, 3H), 1.54 (dd, J=9.2, 5.5 Hz,3H). ESMS (M+H)=373.23.

Compound 276:(7S)-2-((trans-3-((5-fluoropyrimidin-2-yl)oxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-155 to provide the title product, 4.5% yield. 1HNMR (300 MHz, CDCl₃) δ 8.30 (s, 2H), 7.92 (s, 1H), 5.30-5.16 (m, 1H),4.89 (d, J=6.3 Hz, 1H), 4.60-4.46 (m, 1H), 4.00 (q, J=6.8 Hz, 1H), 2.96(s, 3H), 2.58 (ddtd, J=9.5, 7.9, 4.0, 1.6 Hz, 2H), 2.44-2.29 (m, 2H),2.13 (s, 3H), 1.32 (d, J=6.8 Hz, 3H). ESMS (M+1)=374.26.

Compound 287:(7S)-2-((trans-3-(3,5-difluoro-4-methoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-104 to provide the title product, 219 mg (84%yield); 1H NMR (300 MHz, CDCl₃) δ 9.57 (s, 1H), 6.36-6.15 (m, 2H), 5.15(d, J=5.9 Hz, 1H), 4.64 (ddd, J=10.7, 7.0, 4.0 Hz, 1H), 4.52-4.34 (m,1H), 3.98 (q, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.93 (d, J=12.3 Hz, 3H), 2.50(ddd, J=12.4, 6.7, 3.7 Hz, 2H), 2.41-2.21 (m, 2H), 2.17 (s, 3H), 1.31(d, J=6.8 Hz, 3H); ESMS (M+H)=420.22.

Compound 291: (7S)-4,7,8-trimethyl-2-((trans3-(2,3,4-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A reaction ofintermediates A-2 and B-106 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 9.03 (s, 1H), 6.76 (tdd, J=9.7, 8.2, 2.5 Hz, 1H),6.51-6.30 (m, 1H), 4.97 (d, J=5.8 Hz, 1H), 4.83-4.67 (m, 1H), 4.58-4.39(m, 1H), 3.99 (q, J=6.8 Hz, 1H), 2.96 (s, 3H), 2.65-2.47 (m, 2H),2.41-2.26 (m, 2H), 2.16 (s, 3H), 1.32 (d, J=6.9 Hz, 3H); ESMS(M+H)=408.21.

Compound 292: (7S)-4,7,8-trimethyl-2-((trans3-(2,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-107 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.17 (td, J=10.6, 7.6 Hz, 1H), 6.90 (dt, J=11.9, 7.8Hz, 1H), 5.48 (s, 1H), 4.90-4.84 (m, 1H), 4.66-4.47 (m, 1H), 4.07 (dt,J=10.6, 4.8 Hz, 1H), 3.06 (d, J=5.1 Hz, 3H), 2.67-2.35 (m, 4H), 2.18 (s,3H), 1.32 (t, J=5.8 Hz, 3H); ESMS (M+H)=408.42.

Compound 295:(7S)-4,7,8-trimethyl-2-((trans-3-(2,4-drifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-108 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 8.37 (s, 1H), 6.94-6.81 (m, 1H), 6.82-6.66 (m, 2H), 5.01(d, J=4.3 Hz, 1H), 4.92-4.76 (m, 1H), 4.67-4.49 (m, 1H), 4.16-4.00 (m,1H), 3.06 (s, 3H), 2.77-2.56 (m, 2H), 2.41 (ddd, J=13.9, 6.2, 4.5 Hz,2H), 2.23 (s, 3H), 1.41 (d, J=6.9 Hz, 3H); ESMS (M+H)=390.15.

Compound 315:(7S)-4,7,8-trimethyl-2-((trans-3-((5-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-110 to provide the title product. 345 mg (55%yield); 1H NMR (400 MHz, Methanol-d4) δ 9.00 (s, 1H), 8.89 (d, J=2.4 Hz,1H), 8.47 (s, 1H), 5.39-5.27 (m, 1H), 4.79-4.66 (m, 1H), 4.33 (q, J=6.9Hz, 1H), 3.25 (s, 3H), 2.91-2.65 (m, 4H), 2.37 (s, 3H), 1.54 (d, J=6.9Hz, 3H); ESMS (M+H)=423.17.

Compound 324:(7S)-4,7,8-trimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-112 to provide the title product. 664 mg (68%yield); 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J=2.7 Hz, 1H), 7.82 (d,J=8.7 Hz, 1H), 7.55 (dd, J=8.7, 2.7 Hz, 1H), 5.19-5.06 (m, 1H),4.73-4.60 (m, 1H), 4.34 (q, J=6.9 Hz, 1H), 3.26 (s, 3H), 2.85-2.60 (m,4H), 2.39 (s, 3H), 1.54 (d, J=6.9 Hz, 3H); ESMS (M+H)=423.24.

Compound 326:(7S)-4,7,8-trimethyl-2-((trans-3-(4-(trifluoromethoxy)phenoxy)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-113 to provide the title product. 309 mg (61%yield); 1H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 7.05 (d, J=8.9 Hz, 2H),6.71 (t, J=6.3 Hz, 2H), 4.86 (d, J=6.0 Hz, 1H), 4.78-4.69 (m, 1H), 4.46(dt, J=13.8, 6.9 Hz, 1H), 4.03-3.91 (m, 1H), 2.54 (ddd, J=13.7, 7.2, 3.3Hz, 2H), 2.39-2.28 (m, 2H), 2.15 (s, 3H), 1.79 (s, 1H), 1.32 (d, J=6.8Hz, 3H); ESMS (M+H)=438.28.

Compound 333:(7S)-4,7,8-trimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-115 to provide the title product. 234 mg (99%yield); 1H NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.42 (s, 2H), 7.08 (s,1H), 5.05 (s, 1H), 4.63 (d, J=6.1 Hz, 1H), 4.28-4.11 (m, 1H), 3.15 (s,3H), 2.67 (s, 4H), 2.36 (s, 3H), 1.52 (d, J=6.7 Hz, 3H); ESMS(M+H)=424.23.

Compound 335:(7S)-4,7,8-trimethyl-2-((trans-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-116 to provide the title product. 314 mg (91%yield); 1H NMR (400 MHz, CDCl₃) δ 9.26 (s, 1H), 8.51 (d, J=5.6 Hz, 1H),7.10 (d, J=2.3 Hz, 1H), 6.83 (dd, J=5.6, 2.3 Hz, 1H), 5.07 (d, J=5.9 Hz,1H), 4.97-4.86 (m, 1H), 4.63-4.44 (m, 1H), 4.06 (q, J=6.8 Hz, 1H), 3.04(d, J=5.7 Hz, 3H), 2.64 (ddt, J=14.0, 7.2, 3.4 Hz, 2H), 2.47 (dt,J=31.8, 12.1 Hz, 2H), 2.25 (s, 3H), 1.39 (d, J=6.8 Hz, 3H); ESMS(M+H)=423.24.

Compound 339:(7S)-4,7,8-trimethyl-2-((trans-3-(p-tolyloxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and B-117 to provide the title product. 204 mg (64%yield); 1H NMR (400 MHz, Methanol-d4) δ 7.05 (d, J=8.2 Hz, 2H), 6.70 (d,J=8.3 Hz, 2H), 4.57 (dd, J=14.0, 7.2 Hz, 1H), 4.28 (q, J=6.9 Hz, 1H),3.22 (s, 3H), 2.57 (dd, J=10.6, 4.7 Hz, 4H), 2.28 (d, J=13.2 Hz, 3H),2.25 (s, 3H), 1.52 (d, J=6.9 Hz, 3H); ESMS (M+H)=368.38.

Compound 340:(7S)-4,7,8-trimethyl-2-((trans-3-(4-(trifluoromethyl)phenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-118 to provide the title product. 141 mg (66%yield); 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J=8.5 Hz, 2H), 6.98 (d,J=8.5 Hz, 2H), 5.04-4.90 (m, 1H), 4.61 (p, J=7.1 Hz, 1H), 4.29 (q, J=6.9Hz, 1H), 3.22 (d, J=4.2 Hz, 3H), 2.64 (ddd, J=6.4, 4.1, 1.5 Hz, 4H),2.31 (s, 3H), 1.52 (d, J=7.0 Hz, 3H); ESMS (M+H)=422.53.

Compound 342:(7S)-2-((trans-3-(4-methoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-119 to provide the title product. 131 mg (64%yield); 1H NMR (400 MHz, Methanol-d4) δ 6.78 (dd, J=29.6, 7.8 Hz, 4H),4.57 (s, 1H), 4.27 (d, J=6.5 Hz, 1H), 3.73 (s, 3H), 3.21 (s, 3H),2.71-2.38 (m, 4H), 2.30 (s, 3H), 1.52 (d, J=6.3 Hz, 3H); ESMS(M+H)=384.37.

Compound 344:(7S)-2-((trans-3-(4-fluoro-2-methoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-120 to provide the title product. 112 mg (59%yield); 1H NMR (400 MHz, Methanol-d4) δ 6.87-6.67 (m, 2H), 6.57 (ddd,J=8.8, 8.3, 2.9 Hz, 1H), 4.87-4.84 (m, 1H), 4.66-4.52 (m, 1H), 4.33-4.23(m, 1H), 3.84 (s, 3H), 3.23 (s, 3H), 2.70-2.57 (m, 2H), 2.51 (ddd,J=18.7, 12.5, 7.2 Hz, 2H), 2.30 (d, J=2.4 Hz, 3H), 1.52 (d, J=6.9 Hz,3H); ESMS (M+H)=402.3.

Compound 347:(7S)-4,7,8-trimethyl-2-((trans-3-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-121 to provide the title product. 170 mg (81%yield); 1H NMR (400 MHz, CDCl₃) δ 9.57 (s, 1H), 7.65-7.56 (m, 1H), 7.16(ddd, J=8.9, 3.0, 1.6 Hz, 1H), 6.77 (dd, J=8.9, 0.9 Hz, 1H), 5.12 (d,J=5.8 Hz, 1H), 4.88-4.74 (m, 1H), 4.74-4.57 (m, 2H), 4.59-4.47 (m, 1H),4.09-3.97 (m, 1H), 3.01 (d, J=1.3 Hz, 3H), 2.70-2.49 (m, 2H), 2.45-2.35(m, 2H), 2.24 (d, J=1.3 Hz, 3H), 1.40-1.31 (m, 3H); ESMS (M+H)=453.27.

Compound 350:(7S)-2-((trans-3-(3-fluoro-4-methoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 andtrans-3-(3-fluoro-4-methoxyphenoxy)cyclobutan-1-amine hydrochloride(Pharmablock) to provide the title product, 127 mg (75% yield); 1H NMR(400 MHz, Methanol-d4) δ 7.06-6.94 (m, 1H), 6.68-6.60 (m, 1H), 6.56(ddd, J=9.0, 2.9, 1.6 Hz, 1H), 4.62-4.52 (m, 1H), 4.33-4.24 (m, 1H),3.80 (s, 3H), 3.22 (s, 3H), 2.62-2.49 (m, 4H), 2.30 (d, J=3.4 Hz, 3H),1.55-1.48 (m, 3H); ESMS (M+H)=402.23.

Compound 352:(7S)-2-((trans-3-(3,4-dimethoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-122 to provide the title product. 2.69 g (97%yield); 1H NMR (400 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.50 (s, 1H), 8.37(d, J=48.2 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.50 (t, J=4.8 Hz, 1H),6.39-6.19 (m, 1H), 4.87-4.71 (m, 1H), 4.62-4.41 (m, 1H), 4.30 (q, J=6.9Hz, 1H), 3.71 (d, J=15.7 Hz, 3H), 3.68 (s, 3H), 3.15 (d, J=14.3 Hz, 3H),2.29 (s, 3H), 1.39 (t, J=7.1 Hz, 3H); ESMS (M+H)=414.28.

Compound 354:(7S)-2-((trans-3-(2-fluoro-4-methoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-123 to provide the title product. 185 mg (83%yield); 1H NMR (400 MHz, Methanol-d4) δ 6.86 (t, J=9.2 Hz, 1H), 6.72(dt, J=20.4, 10.2 Hz, 1H), 6.63 (ddd, J=9.0, 2.9, 1.5 Hz, 1H), 4.88-4.83(m, 1H), 4.65-4.56 (m, 1H), 4.28 (q, J=6.9 Hz, 1H), 3.74 (s, 3H), 3.23(s, 3H), 2.67-2.58 (m, 2H), 2.57-2.44 (m, 2H), 2.30 (s, 3H), 1.52 (d,J=7.0 Hz, 3H); ESMS (M+H)=402.26.

Compound 357:(7S)-2-((trans-3-((6-fluoropyridin-3-yl)oxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-124 to provide the title product. 124 mg (45%yield); 1H NMR (400 MHz, Methanol-d4) δ 7.73 (dd, J=3.0, 1.6 Hz, 1H),7.49-7.39 (m, 1H), 6.99 (dd, J=8.9, 3.1 Hz, 1H), 4.98-4.88 (m, 1H), 4.61(p, J=7.0 Hz, 1H), 4.35-4.23 (m, 1H), 3.22 (s, 3H), 2.67-2.56 (m, 4H),2.31 (s, 3H), 1.51 (d, 7.0 Hz, 3H); ESMS (M+H)=373.31.

Compound 359:(7S)-2-((trans-3-(3-fluoro-4-(trifluoromethoxy)phenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-125 to provide the title product. 171 mg (53%yield); 1H NMR (400 MHz, Methanol-d4) δ 7.30 (td, J=9.0, 1.0 Hz, 1H),6.84-6.78 (m, 1H), 6.75-6.65 (m, 1H), 4.97-4.85 (m, 1H), 4.66-4.55 (m,1H), 4.34-4.24 (m, 1H), 3.22 (s, 3H), 2.62 (dt, J=6.4, 5.1 Hz, 4H), 2.30(d, J=3.6 Hz, 3H), 1.52 (dd, J=6.9, 3.6 Hz, 3H); ESMS (M+H)=456.31.

Compound 361:(7S)-2-((trans-3-((6-(difluoromethoxy)pyridin-3-yl)oxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

Prepared by reaction of intermediates A-2 and B-126 to provide the titleproduct, 161 mg (64% yield); 1H NMR (400 MHz, Methanol-d4) δ 7.77 (d,J=2.9 Hz, 1H), 7.39 (dd, J=8.6, 2.8 Hz, 1H), 7.28 (T, J=73.5 Hz, 1H),6.92 (d, J=8.9 Hz, 1H), 4.97-4.88 (m, 1H), 4.59 (dt, J=14.4, 7.1 Hz,1H), 4.33-4.23 (m, 1H), 3.22 (s, 3H), 2.81-2.50 (m, 4H), 2.31 (s, 3H),1.52 (d, J=6.9 Hz, 3H); ESMS (M+H)=421.18.

Compound 370:(7S)-2-((trans-3-(4-fluoro-3-methoxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-127 to provide the title product. 161 mg (70%yield); 1H NMR (400 MHz, Methanol-d4) δ 6.96 (dd, J=11.2, 8.9 Hz, 1H),6.58 (dd, J=7.2, 2.9 Hz, 1H), 6.30 (dt, J=8.9, 3.1 Hz, 1H), 4.57 (dd,J=13.8, 7.2 Hz, 1H), 4.31-4.24 (m, 1H), 3.83 (s, 3H), 3.22 (s, 3H),2.61-2.54 (m, 4H), 2.30 (s, 3H), 1.52 (d, J=6.9 Hz, 3H); ESMS(M+H)=402.36.

Compound 303:(7S)-2-((trans-3-((4-fluorophenyl)thio)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-109 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.39-7.29 (m, 2H), 7.12-7.02 (m, 2H), 4.60 (p, J=7.5Hz, 1H), 4.28 (q, J=6.9 Hz, 1H), 3.96-3.82 (m, 1H), 3.21 (s, 3H),2.67-2.52 (m, 2H), 2.41 (ddd, J=11.9, 7.9, 3.7 Hz, 2H), 2.28 (d, J=3.1Hz, 3H), 1.51 (d, J=6.9 Hz, 3H); ESMS (M+1)=388.17.

Compound 317:(7S)-4,7,8-trimethyl-2-((trans-3-((4-(trifluoromethyl)phenyl)thio)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-111 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 7.88 (s, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.17 (d, J=8.3 Hz,2H), 4.83 (d, J=6.8 Hz, 1H), 4.67-4.57 (m, 1H), 4.03-3.96 (m, 1H),3.93-3.83 (m, 1H), 2.96 (s, 3H), 2.54-2.35 (m, 4H), 2.13 (s, 3H), 1.32(d, J=6.8 Hz, 3H). ESMS (M+1)=438.2.

Compound 329:(7S)-4,7,8-trimethyl-2-((trans-3-((3,4,5-trifluorophenyl)thio)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-114 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.10-6.92 (m, 2H), 4.68 (p, J=7.5 Hz, 1H), 4.30 (q,J=6.9 Hz, 1H), 4.09-3.97 (m, 1H), 3.23 (s, 3H), 2.82-2.63 (m, 2H),2.52-2.35 (m, 2H), 2.33 (s, 3H), 1.53 (d, J=6.9 Hz, 3H); ESMS(M+1)=424.23.

Compound 349:(7S)-2-((trans-3-(3,5-difluoro-4-hydroxyphenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

A 1 M solution of Boron tribromide (1.9 ml, 1.9 mmol) was added toCompound 287 (105 mg, 0.24 mmol) and stirred at room temperature for 16hours. Methanol was added to the mixture then evaporated in vacuo toprovide the crude product. The crude was purified by reverse phasechromatography to provide 5.5 mg of the title product. 1H NMR (400 MHz,Methanol-d4) δ 6.50-6.37 (m, 2H), 4.80-4.72 (m, 1H), 4.62-4.51 (m, 1H),4.29 (q, J=6.9 Hz, 1H), 3.22 (d, J=6.2 Hz, 3H), 2.64-2.45 (m, 4H),2.33-2.28 (m, 3H), 1.52 (d, J=7.0 Hz, 3H). ESMS (M+1)=406.18.

2F. Preparation of Compounds of Table 9A

Compound 253:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

(7S)-2-chloro-4,5,7,8-tetramethyl-7H-pteridin-6-one (A-3) (2.15 g, 8.94mmol) and trans-3-(3,4,5-trifluorophenoxy)cyclobutan-1-aminehydrochloride (B-101) (2.25 g, 8.89 mmol) was taken into 20 ml ofn-butanol and refluxed for 20 hours. The reaction was evaporated invacuo to give the crude residue. The crude was dissolved indichloromethane (a flocculent material seen in the solution) andfiltered over a plug of silica gel eluting with 3% methanol indichloromethane. The filtrate was evaporated in vacuo to afford an oilthat turned into a crunchy foam, wt 2.1 g. 1H (CDCl₃, 300 MHz) δ6.44-6.38 (m, 2H), 5.37 (br s, 1H), 4.76-4.54 (m, 1H), 4.58-4.54 (m,1H), 4.0 (q, J=6.9 Hz, 1H), 3.30 (s, 3H), 3.02 (s, 3H), 2.64-2.55 (m,2H), 2.49-2.37 (m, 2H), 2.37 (s, 3H), 1.21 (d, J=6.9 Hz, 3H). ChiralHPLC (ChiralPak IB column; 25% EtOH/hexanes; isocratic): Rt 10.283 mins.(94% ee).

TABLE 9A Compound # L₂-Ring B M + 1 Comp 353

428.31 Comp 343

398.37 Comp 355

416.36 Comp 351

416.29 Comp 338

382.38 Comp 358

387.32 Comp 345

416.29 Comp 346

467.33 Comp 250

386.33 Comp 274

388.36 Comp 314

437.17 Comp 325

452.28 Comp 362

435.21 Comp 373

416.31 Comp 337

437.33 Comp 334

438.28 Comp 323

437.29 Comp 341

436.33 Comp 360

470.32 Comp 296

404.2 Comp 252

404.38 Comp 253

422.22 Comp 293

422.2 Comp 294

422.2 Comp 307

402.17 Comp 320

452.2 Comp 330

438.23

Compound 353:(7S)-2-((trans-3-(3,4-dimethoxyphenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-122 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 6.83 (d,J=8.8 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H), 6.31 (dd, J=8.7, 2.8 Hz, 1H),4.84-4.79 (m, 1H), 4.60 (p, J=7.0 Hz, 1H), 4.28 (q, J=7.0 Hz, 1H), 3.80(s, 3H), 3.76 (s, 3H), 3.32 (d, J=3.3 Hz, 3H), 3.22 (s, 3H), 2.64-2.53(m, 4H), 2.48 (s, 3H), 1.37 (d, J=7.0 Hz, 3H); ESMS (M+H)=428.31.

Compound 343:(7S)-2-((trans-3-(4-methoxyphenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-119 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 6.86-6.80 (m,2H), 6.78-6.72 (m, 2H), 4.84-4.76 (m, 1H), 4.60 (p, J=7.0 Hz, 1H), 4.28(q, J=7.0 Hz, 1H), 3.73 (s, 3H), 3.34-3.31 (m, 3H), 3.21 (s, 3H), 2.54(tdd, J=8.7, 7.9, 3.3 Hz, 4H), 2.48 (s, 3H), 1.36 (d, J=7.0 Hz, 3H);ESMS (M+H)=398.37.

Compound 355:(7S)-2-((trans-3-(2-fluoro-4-methoxyphenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-123 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 6.85 (t,J=9.3 Hz, 1H), 6.70 (dd, J=12.9, 2.9 Hz, 1H), 6.66-6.52 (m, 1H),4.66-4.52 (m, 1H), 4.27 (q, J=7.0 Hz, 1H), 3.73 (s, 3H), 3.34-3.31 (m,3H), 3.22 (s, 3H), 2.66-2.49 (m, 4H), 2.48 (s, 3H), 1.37 (d, J=7.0 Hz,3H); ESMS (M+H)=416.36.

Compound 351:(7S)-2-((trans-3-(3-fluoro-4-methoxyphenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediate A-3 and(trans)-3-(4-fluoro-3-methoxyphenoxy)cyclobutan-1-amine hydrochloride toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 6.98 (t,J=9.3 Hz, 1H), 6.68-6.60 (m, 1H), 6.61-6.48 (m, 1H), 4.83-4.77 (m, 1H),4.59 (p, J=7.0 Hz, 1H), 4.28 (q, J=7.0 Hz, 1H), 3.80 (s, 3H), 3.34-3.31(m, 3H), 3.21 (s, 3H), 2.58 (dt, J=8.3, 4.9 Hz, 4H), 2.48 (s, 3H), 1.37(d, J=7.0 Hz, 3H); ESMS (M+H)=416.29.

Compound 338:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(p-tolyloxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-117 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.11-7.00 (m,2H), 6.77-6.64 (m, 2H), 4.60 (p, J=7.0 Hz, 1H), 4.28 (q, J=7.0 Hz, 1H),3.33-3.31 (m, 3H), 3.22 (s, 3H), 2.63-2.51 (m, 4H), 2.48 (s, 3H), 2.25(s, 3H), 1.36 (t, J=5.9 Hz, 3H); ESMS (M+H)=382.38.

Compound 358: (7S)-2-((trans3-((6-fluoropyridin-3-yl)oxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-124 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.73 (dd,J=2.8, 1.7 Hz, 1H), 7.53-7.40 (m, 1H), 6.99 (dd, J=8.9, 2.9 Hz, 1H),4.98-4.92 (m, 1H), 4.64 (p, J=7.1 Hz, 1H), 4.29 (q, J=7.0 Hz, 1H), 3.34(s, 3H), 3.23 (s, 3H), 2.73-2.57 (m, 4H), 2.49 (s, 3H), 1.37 (d, J=7.0Hz, 3H); ESMS (M+H)=387.32.

Compound 345:(7S)-2-((trans-3-(4-fluoro-2-methoxyphenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-120 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 6.84-6.67 (m,2H), 6.57 (td, J=8.5, 2.9 Hz, 1H), 4.68-4.55 (m, 1H), 4.34-4.22 (m, 1H),3.83 (d, J=7.4 Hz, 3H), 3.34-3.30 (m, 3H), 3.23 (s, 2H), 2.71-2.50 (m,4H), 2.48 (d, J=2.4 Hz, 3H), 1.37 (d, J=7.0 Hz, 3H); ESMS (M+H)=416.29.

Compound 346:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-121 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.71 (d,J=3.0 Hz, 1H), 7.33 (dd, J=8.9, 3.0 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H),4.76 (q, J=8.8 Hz, 2H), 4.63 (p, J=7.0 Hz, 1H), 4.29 (q, J=7.0 Hz, 1H),3.36-3.32 (m, 3H), 3.23 (d, J=4.5 Hz, 3H), 2.71-2.53 (m, 4H), 2.49 (s,3H), 1.37 (d, J=7.0 Hz, 3H); ESMS (M+H)=467.33.

Compound 250:(7S)-2-((trans-3-(4-fluorophenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-109 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.07-6.95 (m,2H), 6.88-6.77 (m, 2H), 4.95-4.83 (m, 1H), 4.70-4.57 (m, 1H), 4.32 (q,J=6.9 Hz, 1H), 3.37-3.33 (m, 3H), 3.24 (s, 3H), 2.72-2.56 (m, 4H), 2.53(s, 3H), 1.39 (d, J=7.0 Hz, 3H); ESMS (M+H)=386.33.

Compound 274:(S)-2-((trans-3-((5-fluoropyrimidin-2-yl)oxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-155 toprovide the title product, 5.2% yield. 1H NMR (300 MHz, CDCl₃) δ 8.39(s, 2H), 5.31 (dq, J=7.5, 4.2, 3.7 Hz, 1H), 4.94 (d, J=6.3 Hz, 1H), 4.64(q, J=7.5, 7.0 Hz, 1H), 4.01 (q, J=6.9 Hz, 1H), 3.30 (s, 3H), 3.01 (s,3H), 2.75-2.59 (m, 2H), 2.55-2.40 (m, 2H), 2.35 (s, 3H), 1.21 (d, J=6.9Hz, 3H); ESMS (M+1)=388.36.

Compound 314(7S)-4,5,7,8-tetramethyl-2-((trans-3-((5-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-110 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 8.96 (s, 1H),8.85 (d, J=2.5 Hz, 1H), 8.42 (s, 1H), 5.36-5.22 (m, 1H), 4.78-4.68 (m,1H), 4.32 (q, J=7.0 Hz, 1H), 3.34 (s, 3H), 3.24 (s, 3H), 2.87-2.68 (m,4H), 2.52 (s, 3H), 1.38 (d, J=7.0 Hz, 3H); ESMS (M+H)=437.17.

Compound 325:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(4-(trifluoromethoxy)phenoxy)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-113 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.19 (d,J=8.5 Hz, 2H), 6.93-6.86 (m, 2H), 4.99-4.87 (m, 1H), 4.70-4.56 (m, 1H),4.36-4.25 (m, 1H), 3.33 (d, J=6.8 Hz, 3H), 3.23 (s, 3H), 2.76-2.55 (m,4H), 2.52 (s, 3H), 1.38 (d, J=7.0 Hz, 3H); ESMS (M+H)=452.28.

Compound 362:(7S)-2-((trans-3-((6-(difluoromethoxy)pyridin-3-yl)oxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-126 toprovide the title product. 1H NMR (400 MHz, Methanol) δ 7.78 (t, J=5.7Hz, 1H), 7.38 (ddd, J=77.7, 69.1, 67.0 Hz, 2H), 6.91 (dt, J=8.9, 1.4 Hz,1H), 4.97-4.90 (m, 1H), 4.70-4.54 (m, 1H), 4.34-4.21 (m, 1H), 3.34-3.29(m, 3H), 3.22 (s, 3H), 2.70-2.55 (m, 4H), 2.48 (d, J=3.5 Hz, 3H), 1.37(d, J=6.6 Hz, 2H); ESMS (M+H)=435.21.

Compound 373:(7S)-2-((trans-3-(4-fluoro-3-methoxyphenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-127 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 6.94 (t,J=9.3 Hz, 1H), 6.65-6.49 (m, 1H), 6.30 (dd, J=6.1, 2.4 Hz, 1H), 4.97 (d,J=35.2 Hz, 4H), 4.85 (s, 1H), 4.58 (s, 1H), 4.28 (d, J=5.6 Hz, 1H), 3.83(s, 3H), 3.34 (s, 3H), 3.22 (s, 3H), 2.56 (d, J=19.1 Hz, 4H), 2.49 (s,3H), 1.38 (d, J=5.5 Hz, 3H); ESMS (M+H)=416.31.

Compound 337:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((2-(trifluoromethyl)pyridin-4-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-116 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d,J=5.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.15-7.05 (m, 1H), 5.11 (ddd,J=23.4, 13.9, 11.1 Hz, 2H), 4.67 (p, J=7.1 Hz, 1H), 4.30 (q, J=7.0 Hz,1H), 3.37-3.32 (m, 3H), 3.23 (s, 3H), 2.82-2.67 (m, 4H), 2.67 (s, 3H),2.50 (d, J=4.3 Hz, 3H), 1.38 (dd, J=6.9, 3.2 Hz, 3H); ESMS (M+H)=437.33.

Compound 334:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-115 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 8.55 (s, 2H),5.17 (p, J=5.2 Hz, 1H), 4.69 (p, J=7.1 Hz, 1H), 4.30 (q, J=7.0 Hz, 1H),3.34 (s, 3H), 3.24 (s, 3H), 2.78-2.67 (m, 4H), 2.50 (s, 3H), 1.38 (d,J=7.0 Hz, 3H); ESMS (M+H)=438.28.

Compound 323:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-112 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 8.37 (d,J=2.7 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 7.61-7.50 (m, 1H), 5.21-5.10 (m,1H), 4.76-4.61 (m, 1H), 4.38-4.26 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H),2.86-2.61 (m, 4H), 2.55 (s, 3H), 1.39 (d, J=7.0 Hz, 3H); ESMS(M+H)=437.29.

Compound 341:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(4-(trifluoromethyl)phenoxy)-cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-118 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d,J=8.7 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 4.98 (p, J=5.2 Hz, 1H), 4.64 (p,J=7.1 Hz, 1H), 4.29 (q, J=7.0 Hz, 1H), 3.32 (d, J=5.4 Hz, 3H), 3.22 (s,3H), 2.66-2.59 (m, 4H), 2.49 (s, 3H), 1.37 (d, J=7.0 Hz, 3H); ESMS(M+H)=436.33.

Compound 360: (7S)-2-((trans3-(3-fluoro-4-(trifluoromethoxy)phenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-125 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.31 (td,J=9.0, 1.0 Hz, 1H), 6.88-6.77 (m, 1H), 6.73 (tdd, J=9.1, 2.9, 1.6 Hz,1H), 4.91 (p, J=5.1 Hz, 1H), 4.69-4.54 (m, 1H), 4.34-4.24 (m, 1H),3.33-3.31 (m, 3H), 3.31 (dd, J=3.3, 1.6 Hz, 3H), 3.22 (d, J=6.4 Hz, 3H),2.70-2.57 (m, 4H), 2.48 (d, J=4.1 Hz, 3H), 1.37 (dd, J=7.0, 2.8 Hz, 3H);ESMS (M+H)=470.32.

Compound 296:(7S)-2-((trans-3-(2,4-difluorophenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-108 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.10-6.77 (m,3H), 4.91 (td, J=6.5, 3.2 Hz, 1H), 4.72-4.53 (m, 1H), 4.29 (q, J=7.0 Hz,1H), 3.32 (d, J=3.1 Hz, 3H), 3.23 (s, 3H), 2.74-2.52 (m, 4H), 2.48 (s,3H), 1.37 (d, J=7.0 Hz, 3H); ESMS (M+H)=404.2.

Compound 252:(7S)-2-((trans-3-(3,4-difluorophenoxy)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-102 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.17 (dd,J=19.5, 9.3 Hz, 1H), 6.85-6.70 (m, 1H), 6.67-6.57 (m, 1H), 4.94-4.83 (m,1H), 4.66-4.53 (m, 1H), 4.32 (q, J=6.9 Hz, 1H), 3.37-3.33 (m, 3H), 3.24(s, 3H), 2.71-2.57 (m, 4H), 2.52 (s, 3H), 1.38 (d, J=7.0 Hz, 3H); ESMS(M+H)=404.38.

Compound 253:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-101 toprovide the title product. 1H NMR (300 MHz, DMSO-d6) δ 7.01 (d, J=6.9Hz, 1H), 6.93-6.78 (m, 2H), 4.84 (dt, J=6.7, 3.2 Hz, 1H), 4.42 (q,J=7.8, 6.9 Hz, 1H), 4.02 (q, J=6.8 Hz, 1H), 3.18 (s, 3H), 2.92 (s, 3H),2.49-2.31 (m, 4H), 2.27 (s, 3H), 1.05 (d, J=6.8 Hz, 3H); ESMS(M+H)=422.22.

Compound 293:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(2,3,4-trifluorophenoxy)cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-106 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.08-6.91 (m,1H), 6.79-6.66 (m, 1H), 4.95 (dt, J=10.9, 5.4 Hz, 1H), 4.71-4.57 (m,1H), 4.35-4.22 (m, 1H), 3.38-3.33 (m, 3H), 3.24 (s, 3H), 2.75-2.56 (m,4H), 2.50 (s, 3H), 1.38 (d, J=7.0 Hz, 3H); ESMS (M+H)=422.2.

Compound 294:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(2,4,5-trifluorophenoxy)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-107 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.26-7.09 (m,1H), 6.94 (dt, J=11.8, 7.8 Hz, 1H), 4.93 (dd, J=10.3, 5.4 Hz, 1H),4.72-4.55 (m, 1H), 4.29 (q, J=7.0 Hz, 1H), 3.36-3.32 (m, 3H), 3.23 (s,3H), 2.72-2.57 (m, 4H), 2.49 (s, 3H), 1.37 (d, J=7.0 Hz, 3H); ESMS(M+H)=422.2.

Compound 307:(7S)-2-((trans-3-((4-fluorophenyl)thio)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-109 toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 7.43-7.26 (m,2H), 7.14-7.00 (m, 2H), 4.62 (p, J=7.6 Hz, 1H), 4.29 (q, J=7.0 Hz, 1H),3.98-3.80 (m, 1H), 3.31 (s, 3H), 3.21 (s, 3H), 2.62 (ddd, J=23.7, 13.4,8.3 Hz, 2H), 2.46 (s, 3H), 2.45-2.34 (m, 2H), 1.36 (d, J=7.0 Hz, 3H);ESMS (M+1)=402.17.

Compound 320:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((4(trifluoromethyl)phenyl)thio)-cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-111 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.55 (d,J=8.3 Hz, 2H), 7.34 (t, J=8.5 Hz, 2H), 5.07 (d, J=61.3 Hz, 3H), 4.72 (p,J=7.4 Hz, 1H), 4.34-4.21 (m, 1H), 4.17-4.01 (m, 1H), 3.33 (s, 3H), 3.21(s, 3H), 2.85-2.69 (m, 2H), 2.52-2.47 (m, 4H), 2.47-2.38 (m, 1H), 1.37(d, J=7.0 Hz, 3H); ESMS (M+1)=452.2.

Compound 330:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((3,4,5-trifluorophenyl)thio)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediates A-3 and B-114 toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 7.10-6.95 (m,2H), 4.71 (p, J=7.5 Hz, 1H), 4.39-4.26 (m, 1H), 4.14-3.98 (m, 1H), 3.35(s, 3H), 3.25 (s, 3H), 2.88-2.68 (m, 2H), 2.52 (d, J=11.4 Hz, 3H),2.50-2.38 (m, 2H), 1.39 (d, J=6.9 Hz, 3H); ESMS (M+1)=438.23.

2G. Preparation of Compounds of Table 9B General Procedure for CompoundsPrepared in Table 9B

Compound 246 (115 mg, 0.28 mmol), an alkyl halide (0.31 mmol), andpotassium carbonate (150 mg, 1.08 mmol) were taken into DMF (5 mL) andstirred at room temperature for 18 hours. TFA (125 μL, 1.622 mmol) wasadded. Purification by reverse MPLC: 100 g C18 column, eluting with10-100% acetonitrile in water (0.1% TFA), desired fractions werecombined and dried to provide a product. The recovered the product wasneutralized by passing through the product from PL-HCO3 MPSPE cartridge(500 mg/6 mL tube capacity 0.9 mmol) to provide the desired product.

TABLE 9B Compound # R₁ 312 Et 381 —CH₂CH₂F 313 —CH₂CF₃ 327 —CD₃ 328—CD₂CD₃

Compound 312:(7S)-5-ethyl-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, CDCl₃) δ 6.48-6.36 (m, 2H), 4.76 (tt, J=7.0, 3.9 Hz,1H), 4.57 (td, J=8.0, 5.8 Hz, 1H), 4.21 (dq, J=14.4, 7.2 Hz, 1H), 3.99(q, J=6.9 Hz, 1H), 3.60 (dd, J=14.0, 7.0 Hz, 1H), 3.02 (s, 3H),2.70-2.54 (m, 2H), 2.47 (td, J=6.3, 3.7 Hz, 2H), 2.36 (s, 3H), 1.25-1.07(m, 6H); ESMS (M+H)=436.13.

Compound 381:(7S)-5-(2-fluoroethyl)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)-cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, CDCl₃) δ 6.42 (ddt, J=9.6, 5.7, 1.0 Hz, 2H), 5.09 (d,J=6.1 Hz, 1H), 4.81-4.42 (m, 5H), 4.09-3.76 (m, 2H), 3.02 (s, 3H),2.70-2.40 (m, 4H), 2.35 (s, 3H), 1.21 (d, J=6.9 Hz, 3H); ESMS(M+H)=454.09.

Compound 313:(7S)-4,7,8-trimethyl-5-(2,2,2-trifluoroethyl)-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, CDCl₃) δ 6.43 (ddt, J=9.5, 5.7, 1.0 Hz, 2H), 5.19 (dq,J=15.6, 9.1 Hz, 1H), 5.03 (s, 1H), 4.76 (tt, J=7.1, 3.8 Hz, 1H), 4.58(td, J=8.1, 5.7 Hz, 2H), 4.24-4.02 (m, 2H), 3.03 (s, 3H), 2.63 (dddd,J=12.4, 7.9, 3.9, 2.0 Hz, 2H), 2.53-2.39 (m, 2H), 2.34 (s, 3H), 1.21 (d,J=7.0 Hz, 3H); ESMS (M+H)=490.19.

Compound 327:(7S)-4,7,8-trimethyl-5-(methyl-d3)-2-((trans-3-(3,4,5-trifluorophenoxy)-cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (400 MHz, CDCl₃) δ 6.46-6.37 (m, 2H), 4.76 (tt, J=7.0, 3.8 Hz,1H), 4.57 (q, J=7.6 Hz, 1H), 4.11-4.00 (m, 1H), 3.06 (d, J=1.1 Hz, 3H),2.61 (td, J=8.7, 4.3 Hz, 2H), 2.50 (s, 2H), 2.41 (d, J=1.1 Hz, 3H), 1.26(dd, J=7.0, 1.1 Hz, 3H); ESMS (M+H)=425.24.

Compound 328:(7S)-5-(ethyl-d5)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (400 MHz, CDCl₃) δ 6.46-6.37 (m, 2H), 4.77 (dq, J=6.8, 3.5 Hz,1H), 4.58 (td, J=8.0, 5.8 Hz, 1H), 4.01 (q, J=6.9 Hz, 1H), 3.05 (s, 3H),2.69-2.56 (m, 2H), 2.55-2.42 (m, 2H), 2.39 (s, 3H), 1.23 (d, J=6.9 Hz,3H); ESMS (M+H)=441.22.

2I. Preparation of Compounds of Table 10

TABLE 10 Synthetic Compound # L₂-Ring B R₁ M + 1 Method Comp 243

H 372.28 B Comp 247

H 408.29 B Comp 304

H 388.2 A Comp 305

Me 402.22 B Comp 321

H 438.16 A Comp 322

Me 450.98 B Comp 332

H 424.19 A Comp 331

Me 438.23 B Comp 336

H 454.26 A Comp 348

Me 468.3 B

Compound 243:(7S)-2-((cis-3-(4-fluorophenoxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-128 to provide the title compound. 1H NMR (300MHz, Methanol-d4) δ 7.00 (t, J=8.7 Hz, 2H), 6.85 (dd, J=9.0, 4.3 Hz,2H), 4.57-4.41 (m, 1H), 4.38-4.13 (m, 2H), 3.26 (d, J=11.7 Hz, 3H), 3.05(dd, J=6.7, 4.2 Hz, 2H), 2.35 (s, 3H), 2.24 (dd, J=18.8, 8.5 Hz, 2H),1.55 (d, J=6.9 Hz, 3H); ESMS (M+1)=372.28.

Compound 247:(7S)-4,7,8-trimethyl-2-((cis-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-2 and B-129 to provide the title compound. 1H NMR (300MHz, Methanol-d4) δ 6.73-6.56 (m, 2H), 4.51 (p, J=6.9 Hz, 1H), 4.30 (q,J=6.9 Hz, 1H), 4.18 (dd, J=16.0, 8.1 Hz, 1H), 3.26 (s, 3H), 3.12-2.90(m, 2H), 2.30 (s, 3H), 2.21 (dt, J=12.3, 8.5 Hz, 2H), 1.53 (d, J=6.9 Hz,3H), 0.60-0.58 (m, 1H); ESMS (M+1)=408.29.

Compound 304:(7S)-2-((cis-3-((4-fluorophenyl)thio)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-130 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.41-7.23 (m, 2H), 7.05 (t, J=8.6 Hz, 2H), 4.46-4.22(m, 2H), 3.63 (d, J=11.9 Hz, 3H), 3.62-3.46 (m, 1H), 3.24 (s, 3H),2.99-2.78 (m, 2H), 2.32 (s, 3H), 2.11 (dd, J=20.3, 9.2 Hz, 2H), 1.52 (d,J=6.8 Hz, 3H).

Compound 305:(7S)-2-((cis-3-((4-fluorophenyl)thio)cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-130 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.35 (dd, J=8.5, 5.3 Hz, 2H), 7.06 (t, J=8.7 Hz,2H), 4.48-4.33 (m, 1H), 4.30 (q, J=6.9 Hz, 1H), 3.70-3.49 (m, 1H), 3.32(s, 3H), 3.24 (s, 3H), 2.98-2.82 (m, 2H), 2.50 (s, 3H), 2.21-2.04 (m,2H), 1.37 (d, J=6.9 Hz, 3H).

Compound 321:(7S)-4,7,8-trimethyl-2-((cis-3-((4-(trifluoromethyl)phenyl)thio)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-131 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 8.12 (s, 1H), 7.43 (d, J=8.2 Hz, 2H), 7.25-7.20 (m, 2H),5.02 (s, 1H), 4.42-4.29 (m, 1H), 4.05-3.94 (m, 1H), 3.61-3.43 (m, 1H),2.98 (s, 3H), 2.96-2.89 (m, 2H), 2.14 (s, 3H), 2.02-1.89 (m, 4H), 1.33(d, J=6.9 Hz, 3H).

Compound 322:(7S)-4,5,7,8-tetramethyl-2-((cis-3-((4-(trifluoromethyl)phenyl)thio)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-131 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.55 (d, J=8.3 Hz, 2H), 7.37 (t, J=8.7 Hz, 2H), 4.93(s, 4H), 4.47 (p, J=8.5 Hz, 1H), 4.29 (q, J=7.0 Hz, 1H), 3.88-3.71 (m,1H), 3.35-3.31 (m, 3H), 3.26 (s, 3H), 3.11-2.94 (m, 2H), 2.48 (s, 3H),2.28-2.12 (m, 2H), 1.37 (d, J=7.0 Hz, 3H).

Compound 332:(7S)-4,7,8-trimethyl-2-((cis-3-((3,4,5-trifluorophenyl)thio)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-132 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.12-7.00 (m, 2H), 4.49-4.36 (m, 1H), 4.30 (q, J=6.9Hz, 1H), 3.80-3.65 (m, 1H), 3.25 (s, 3H), 3.00 (dt, J=11.3, 7.2 Hz, 2H),2.30 (s, 3H), 2.14 (dd, J=20.2, 9.1 Hz, 2H), 1.52 (d, J=6.9 Hz, 3H).

Compound 331:(7S)-4,5,7,8-tetramethyl-2-((cis-3-((3,4,5-trifluorophenyl)thio)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-132 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.05 (dd, J=7.8, 6.7 Hz, 2H), 4.57-4.42 (m, 1H),4.40-4.26 (m, 1H), 3.87-3.69 (m, 1H), 3.35 (s, 3H), 3.27 (d, J=12.2 Hz,3H), 3.03 (s, 2H), 2.54 (s, 3H), 2.29-2.12 (m, 2H), 1.40 (d, J=6.8 Hz,3H).

Compound 336:(7S)-4,7,8-trimethyl-2-((cis-3-((4-(trifluoromethoxy)phenyl)thio)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-133 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 9.70 (s, 1H), 7.26 (dd, J=11.7, 4.8 Hz, 2H), 7.10 (d,J=8.7 Hz, 2H), 5.15 (d, J=7.7 Hz, 1H), 4.43-4.27 (m, 1H), 4.02 (q, J=6.8Hz, 1H), 3.55-3.39 (m, 1H), 2.97 (d, J=23.2 Hz, 3H), 2.90 (tt, J=27.9,13.9 Hz, 2H), 2.24 (s, 3H), 1.95 (dd, J=20.7, 9.3 Hz, 2H), 1.36 (d,J=6.8 Hz, 3H).

Compound 348:(7S)-4,5,7,8-tetramethyl-2-((cis-3-((4-(trifluoromethoxy)phenyl)thio)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-133 to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 7.45-7.28 (m, 2H), 7.26-7.11 (m, 2H), 4.47-4.34 (m,1H), 4.29 (q, J=7.0 Hz, 1H), 3.69 (tt, J=9.3, 7.4 Hz, 1H), 3.33-3.31 (m,4H), 3.24 (s, 3H), 3.05-2.86 (m, 2H), 2.46 (s, 3H), 2.24-2.06 (m, 2H),1.37 (d, J=7.0 Hz, 3H).

2J. Preparation of Compounds of Table 11

The compounds were prepared in a similar manner as those for thecompounds of Table 10 above.

TABLE 11 Compound # R₅ Method 240

B 241

B 249

B 251

B

Compound 240:(7S)-2-((trans-3-(4-fluorophenoxy)cyclobutyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-1 and B-100 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.24 (s, 1H), 7.06-6.94 (m, 2H), 6.87-6.75 (m, 2H),4.87-4.78 (m, 1H), 4.51 (s, 1H), 4.33 (q, J=6.9 Hz, 1H), 3.23 (s, 3H),2.58 (dd, J=12.1, 6.5 Hz, 4H), 1.56 (d, J=6.9 Hz, 3H); ESMS(M+1)=358.28.

Compound 241:(7S)-2-((cis-3-(4-fluorophenoxy)cyclobutyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-1 and B-128 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.23 (s, 1H), 6.99 (t, J=8.7 Hz, 2H), 6.84 (dd,J=9.1, 4.3 Hz, 2H), 4.50 (p, J=6.8 Hz, 1H), 4.34 (q, J=6.8 Hz, 1H), 4.14(s, 1H), 3.25 (d, J=9.2 Hz, 3H), 3.04 (d, J=5.4 Hz, 2H), 2.19 (dd,J=19.0, 8.7 Hz, 2H), 1.57 (d, J=6.9 Hz, 3H); ESMS (M+1)=358.29.

Compound 249:(7S)-7,8-dimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-1 and B-101 to provide the title product. 1H NMR (300MHz, EtOD) δ 7.23 (s, 1H), 6.70-6.54 (m, 2H), 4.85 (dd, J=8.7, 3.5 Hz,1H), 4.53 (s, 1H), 4.34 (q, J=6.9 Hz, 1H), 3.24 (s, 3H), 2.61 (dd,J=6.9, 5.4 Hz, 4H), 1.57 (d, J=7.0 Hz, 3H); ESMS (M+1)=394.29.

Compound 251:(7S)-4,7,8-trimethyl-2-((trans-3-(3,4-difluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-1 and B-102 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.23 (s, 1H), 7.16 (dd, J=19.4, 9.3 Hz, 1H), 6.76(ddd, J=12.3, 6.6, 2.8 Hz, 1H), 6.62 (dd, J=6.4, 2.6 Hz, 1H), 4.86 (d,J=5.0 Hz, 1H), 4.55 (d, J=22.0 Hz, 1H), 4.34 (q, J=6.7 Hz, 1H), 3.24 (s,3H), 2.60 (t, J=5.9 Hz, 4H), 1.57 (d, J=6.8 Hz, 3H); ESMS (M+1)=376.24.

2K Preparation of Compounds of Table 12

TABLE 12 Compound L₂-RingB M + 1 Comp 257

422.29 Comp 271

404.29 Comp 261

386.33 Comp 277

411.31 Comp 263

387.32 Comp 270

387.36 Comp 275

410.27

Compound 257:(7S)-4,7,8-Trimethyl-2-((cis-3-((3,4,5-trifluorophenoxy)methyl)cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-134 to afford the title product. 1H NMR (300MHz, Methanol-d4) δ 6.72 (dt, J=13.5, 6.7 Hz, 2H), 4.46-4.37 (m, 1H),4.31 (q, J=6.9 Hz, 1H), 3.95 (d, J=5.1 Hz, 2H), 3.26 (s, 3H), 2.66-2.45(m, 3H), 2.34 (s, 3H), 2.09-1.91 (m, 2H), 1.54 (d, J=6.9 Hz, 3H); ESMS(M+1)=422.29.

Compound 271:(7S)-2-((cis-3-((3,4-difluorophenoxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-138 to afford the title product. 1H NMR (300MHz, Methanol-d4) δ 7.25-7.05 (m, 1H), 6.93-6.79 (m, 1H), 6.77-6.61 (m,1H), 4.47-4.33 (m, 1H), 4.28 (dd, J=13.8, 6.9 Hz, 1H), 3.93 (d, J=4.4Hz, 2H), 3.24 (s, 3H), 2.68-2.43 (m, 3H), 2.32 (d, J=16.1 Hz, 3H),2.05-1.88 (m, 2H), 1.52 (d, J=6.0 Hz, 3H); ESMS (M+1)=404.29.

Compound 261:(7S)-2-((cis-3-((4-fluorophenoxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-135 to afford the title product. 1H NMR (300MHz, Methanol-d4) δ 5.51-5.30 (m, 4H), 2.90-2.81 (m, 1H), 2.76 (q, J=7.0Hz, 1H), 2.40 (d, J=5.4 Hz, 2H), 1.71 (s, 3H), 1.14-0.92 (m, 3H), 0.78(s, 3H), 0.54-0.39 (m, 2H), −0.01 (d, J=6.9 Hz, 3H); ESMS (M+1)=386.33.

Compound 277:5-fluoro-2-((cis-3-(((7S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)methoxy)benzonitrile

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-140 to afford the title product. 1H NMR (300MHz, CDCl₃) δ 8.66 (s, 1H), 7.29-7.20 (m, 2H), 6.91 (dd, J=9.0, 4.1 Hz,1H), 4.92 (d, J=7.8 Hz, 1H), 4.49-4.30 (m, 1H), 4.08 (dt, J=10.0, 5.0Hz, 1H), 4.02 (d, J=5.5 Hz, 2H), 3.05 (s, 3H), 2.79-2.42 (m, 4H), 2.23(s, 3H), 1.95-1.74 (m, 2H), 1.40 (d, J=6.9 Hz, 3H); ESMS (M+1)=411.31.

Compound 263:(7S)-2-((cis-3-(((5-fluoropyridin-3-yl)oxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-136 to afford the title product. 1H NMR (300MHz, Methanol-d4) δ 8.66 (s, 2H), 8.30 (d, J=9.6 Hz, 1H), 4.44 (d,J=25.4 Hz, 1H), 4.32 (s, 3H), 3.27 (s, 3H), 2.66 (s, 3H), 2.35 (s, 4H),2.10 (d, J=5.1 Hz, 2H), 1.54 (d, J=6.4 Hz, 3H).

Compound 270:(7S)-2-((cis-3-(((6-fluoropyridin-3-yl)oxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-137 to afford the title product. 1H NMR (300MHz, Methanol-d4) δ 7.82 (d, J=1.0 Hz, 1H), 7.63-7.45 (m, 1H), 6.98 (dd,J=8.8, 2.6 Hz, 1H), 4.38 (dd, J=15.4, 7.7 Hz, 1H), 4.35-4.20 (m, 1H),4.03 (d, J=4.5 Hz, 2H), 3.25 (s, 3H), 2.72-2.47 (m, 3H), 2.30 (s, 3H),1.99 (dd, J=17.5, 9.0 Hz, 2H), 1.52 (d, J=6.8 Hz, 3H); ESMS(M+1)=387.36.

Compound 275:(7S)-4,7,8-trimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-139 to afford the title product. 1H NMR (300MHz, CDCl₃) δ 9.62 (s, 1H), 7.36 (d, J=1.2 Hz, 1H), 6.47 (d, J=2.0 Hz,1H), 4.94 (d, J=7.5 Hz, 1H), 4.28 (dt, J=14.8, 7.4 Hz, 1H), 4.15 (d,J=5.9 Hz, 2H), 3.98 (dd, J=16.7, 10.0 Hz, 1H), 2.98 (s, 3H), 2. 62-2.38(m, 3H), 2.20 (s, 3H), 1.72-1.50 (m, 2H), 1.32 (t, J=9.9 Hz, 3H); ESMS(M+1)=410.27.

2L. Preparation of Compounds of Table 13

Compound 284:(7S)-2-((cis-3-((3,5-difluoro-4-methoxyphenoxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneStep 1:(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-chloro-4,7,8-trimethyl-5,7-dihydropteridin-6-one (2.96 g, 13.05mmol), cis-3-aminocyclobutyl)methanol hydrochloride (1.796 g, 13.05mmol) and tBuXPhos palladacycle (358.5 mg, 0.5220 mmol) were taken intot-butanol (50 mL) and degassed. A 2M solution of sodium t-butoxide (23mL, 45.70 mmol) was added to the mixture under nitrogen. After stirringat room temperature for 2 hours, ethyl acetate (100 ml) and water wasadded to the reaction mixture. The organic layers separated and theaqueous extracted with ethyl acetate (3×50 ml). The combined extractswere dried over anhydrous sodium sulfate, filtered, and evaporated invacuo to afford the crude product. The crude product was purified bycolumn chromatography (SiO₂) eluting with a gradient of 0-20% methanolin dichloromethane to afford 1.07 g (25% yield) of the title product. 1HNMR (300 MHz, CDCl₃) δ 9.30 (s, 1H), 9.01 (s, 1H), 5.04 (t, J=10.9 Hz,1H), 4.39-4.24 (m, 1H), 4.05 (q, J=6.8 Hz, 1H), 3.60 (d, J=5.9 Hz, 2H),3.04 (s, 3H), 2.87-2.57 (m, 2H), 2.59-2.40 (m, 3H), 2.23 (s, 4H),1.79-1.58 (m, 2H), 1.38 (d, J=6.8 Hz, 3H). ESMS (M+1)=292.24.

Step 2:(7S)-2-((cis-3-((3,5-difluoro-4-methoxyphenoxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

A mixture of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(160 mg, 0.5 mmol), 3,5-difluoro-4-methoxyphenol (166 mg, 1.04 mmol),and triphenylphosphine 272 mg, 1.04 mmol) was taken into 5 ml of THF.Diethylazodicarboxylate (1.038 mmol) was added to the mixture dropwisethen heated to 50° C. for 12 hours. The reaction was evaporated in vacuoand the resulting residue purified by column chromatography (C18 MPLC;0-100% acetonitrile/water (0.1% TFA)). The desired fractions werelyophilized to provide 45 mg (18% yield) of the title product. 1H NMR(300 MHz, Methanol-d4) δ 6.66-6.50 (m, 2H), 4.46-4.34 (m, 1H), 4.28 (q,J=6.9 Hz, 1H), 3.92 (d, J=5.3 Hz, 2H), 3.84 (s, 3H), 3.22 (d, J=12.4 Hz,3H), 2.63-2.43 (m, 3H), 2.29 (s, 3H), 1.96 (dd, J=17.7, 9.0 Hz, 2H),1.52 (d, J=6.9 Hz, 3H); ESMS (M+1)=434.26.

TABLE 13 Comp # L₂-Ring B M + 1 Comp 284

434.26 Comp 282

420.18 Comp 281

422.2 Comp 285

422.37 Comp 258 (trans)

Comp 367

421.26 Comp 369 (trans)

437.29 Comp 366

403.25 Comp 365

451.29 Comp 364

437.29 Comp 363

437.29 Comp 356

437.29 Comp 283

392.18 Comp 280

458.17 Comp 279

360.17

Compounds 282, 281, 285, 258, 367, 369, 366, 365, 364, 363, 356, 283,280, and 279 were prepared in a similar manner by reaction of either(7S)-2-((trans-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneor(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(see Compound 284, Step 1) and a phenol or pyrazole derivative asreported in the procedure for Compound 284.

Compound 282:(7S)-2-((cis-3-((2-chloro-4-fluorophenoxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 2-chloro-4-fluorophenol to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.17 (dd, J=8.2, 2.8 Hz, 1H), 7.09-6.92 (m, 2H),4.43-4.33 (m, 1H), 4.28 (q, J=7.0 Hz, 1H), 4.01 (d, J=4.8 Hz, 2H), 3.22(d, J=10.9 Hz, 3H), 2.66-2.51 (m, 3H), 2.29 (s, 3H), 2.12-1.96 (m, 2H),1.52 (d, J=6.9 Hz, 3H); ESMS (M+1)=420.18.

Compound 281:(7S)-4,7,8-trimethyl-2-((cis-3-((2,3,4-trifluorophenoxy)methyl)cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 2,3,4-trifluorophenol to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 7.08-6.94 (m, 1H), 6.95-6.80 (m, 1H), 4.37 (d, J=8.0 Hz,1H), 4.29 (dd, J=13.9, 6.9 Hz, 1H), 4.05 (d, J=4.9 Hz, 2H), 3.25 (s,3H), 2.68-2.51 (m, 3H), 2.29 (s, 3H), 1.97 (d, J=8.3 Hz, 2H), 1.52 (d,J=6.9 Hz, 3H). ESMS (M+1)=422.2.

Compound 285:(7S)-4,7,8-trimethyl-2-((cis-3-((2,4,5-trifluorophenoxy)methyl)cyclobutyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 2,4,5-trifluorophenol to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 7.14 (ddt, J=15.6, 12.0, 7.8 Hz, 2H), 4.47-4.34 (m, 1H),4.29 (q, J=6.9 Hz, 1H), 4.02 (d, J=5.2 Hz, 2H), 3.24 (s, 3H), 2.70-2.43(m, 4H), 2.29 (s, 3H), 2.06-1.88 (m, 2H), 1.52 (d, J=6.9 Hz, 3H). ESMS(M+1)=422.37.

Compound 258:(7S)-4,7,8-trimethyl-2-((trans-3-((3,4,5-trifluorophenoxy)methyl)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((trans-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 3,4,5-trifluorophenol to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 6.72 (dt, J=13.5, 6.7 Hz, 2H), 4.46-4.37 (m, 1H), 4.31(q, J=6.9 Hz, 1H), 3.95 (d, J=5.1 Hz, 2H), 3.26 (s, 3H), 2.66-2.45 (m,3H), 2.34 (s, 3H), 2.09-1.91 (m, 2H), 1.54 (d, J=6.9 Hz, 3H); ESMS(M+1)=422.34

Compound 367:(7S)-2-((cis-3-(((6-chloro-5-fluoropyridin-3-yl)oxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 3-hydroxy-5-fluoro-6-chloropyridine to provide the title product. 1HNMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 7.86 (t, J=6.2 Hz, 1H), 6.98 (dd,J=9.4, 2.5 Hz, 1H), 4.87 (d, J=7.5 Hz, 1H), 4.39-4.23 (m, 1H), 4.05-3.92(m, 1H), 3.90 (t, J=5.0 Hz, 2H), 2.95 (d, J=12.5 Hz, 3H), 2.60-2.48 (m,2H), 2.48-2.34 (m, 1H), 2.17 (s, 3H), 1.80-1.62 (m, 2H), 1.31 (d, J=6.8Hz, 3H). ESMS (M+1)=421.26.

Compound 369:(7S)-4,7,8-trimethyl-2-((trans-3-(((4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((trans-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 2-hydroxy-4-trifluoromethylpyridine to provide the title product. 1HNMR (400 MHz, Methanol-d4) δ 8.36 (d, J=5.3 Hz, 1H), 7.20 (d, J=5.3 Hz,1H), 7.06 (s, 1H), 4.57 (p, J=7.8 Hz, 1H), 4.48 (d, J=6.8 Hz, 2H), 4.29(q, J=6.9 Hz, 1H), 3.22 (s, 3H), 2.78 (dd, J=8.7, 4.5 Hz, 1H), 2.42(ddd, J=11.9, 9.1, 5.1 Hz, 2H), 2.36-2.31 (m, 1H), 2.30 (s, 3H), 1.52(d, J=6.9 Hz, 3H). ESMS (M+1)=437.29.

Compound 366:(7S)-2-((cis-3-(((5-chloropyridin-3-yl)oxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 3-hydroxy-5-chloropyridine to provide the title product. 1H NMR (400MHz, Methanol-d4) δ 8.36 (d, J=5.3 Hz, 1H), 7.20 (d, J=5.3 Hz, 1H), 7.06(s, 1H), 4.57 (p, J=7.8 Hz, 1H), 4.48 (d, J=6.8 Hz, 2H), 4.29 (q, J=6.9Hz, 1H), 3.22 (s, 3H), 2.78 (dd, J=8.7, 4.5 Hz, 1H), 2.42 (ddd, J=11.9,9.1, 5.1 Hz, 2H), 2.36-2.31 (m, 1H), 2.30 (s, 3H), 1.52 (d, J=6.9 Hz,3H). ESMS (M+1)=403.25.

Compound 365:(7S)-4,7,8-trimethyl-2-((cis-3-(((6-methyl-4-(trifluoromethyl)pyridin-2-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 6-methyl-4-(trifluoromethyl)pyridin-2-ol to provide the titleproduct. 1H NMR (400 MHz, Methanol-d4) δ 7.60-7.45 (m, 1H), 7.05 (s,1H), 6.85 (s, 1H), 4.48-4.15 (m, 4H), 3.25 (d, J=8.5 Hz, 3H), 2.73-2.52(m, 3H), 2.51 (s, 3H), 2.34 (s, 3H), 2.10-1.90 (m, 2H), 1.53 (d, J=6.9Hz, 3H). ESMS (M+1)=451.29.

Compound 364:(7S)-4,7,8-trimethyl-2-((cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 6-(trifluoromethyl)pyridin-3-ol to provide the title product. 1H NMR(400 MHz, CDCl₃) δ 9.17 (s, 1H), 8.30 (s, 1H), 7.50 (t, J=14.0 Hz, 1H),7.24-7.11 (m, 1H), 4.89 (d, J=7.3 Hz, 1H), 4.38-4.23 (m, 1H), 3.97 (dd,J=16.4, 5.4 Hz, 3H), 2.95 (d, J=13.4 Hz, 3H), 2.67-2.31 (m, 4H), 2.17(s, 3H), 1.71 (d, J=7.8 Hz, 2H), 1.31 (d, J=6.3 Hz, 3H). ESMS(M+1)=437.29.

Compound 363:(7S)-4,7,8-trimethyl-2-((cis-3-(((5-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 5-(trifluoromethyl)pyridin-3-ol to provide the title product. 1H NMR(400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.50 (s, 1H), 7.73 (d, J=24.0 Hz,1H), 4.43 (s, 1H), 4.27 (t, J=14.7 Hz, 1H), 4.17 (s, 2H), 3.25 (s, 3H),2.62 (s, 3H), 2.31 (s, 3H), 2.04 (s, 2H), 1.53 (d, J=5.1 Hz, 3H). ESMS(M+1)=437.29.

Compound 356:(7S)-4,7,8-trimethyl-2-((cis-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 5-(trifluoromethyl)pyridin-2-ol to provide the title product. 1H NMR(400 MHz, Methanol-d4) δ 8.47 (d, J=6.1 Hz, 1H), 7.44 (d, J=4.3 Hz, 2H),4.47 (t, J=5.8 Hz, 2H), 4.46-4.40 (m, 1H), 4.31 (q, J=6.9 Hz, 1H), 3.25(d, J=7.2 Hz, 3H), 2.63 (t, J=5.9 Hz, 2H), 2.33 (s, 3H), 2.05 (d, J=8.1Hz, 2H), 1.53 (d, J=6.9 Hz, 3H). ESMS (M+1)=437.29.

Compound 283:(7S)-2-((cis-3-((3-ethynylphenoxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 3-ethynylphenol to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 7.23 (t, J=7.9 Hz, 1H), 7.01 (dd, J=8.1, 5.0 Hz, 2H),6.94 (dd, J=8.3, 2.4 Hz, 1H), 4.36 (dd, J=14.8, 6.9 Hz, 1H), 4.29 (q,J=6.9 Hz, 1H), 3.97 (d, J=5.2 Hz, 2H), 3.45 (s, 1H), 3.22 (d, J=13.4 Hz,3H), 2.63-2.50 (m, 3H), 2.29 (s, 3H), 1.98 (dd, J=17.1, 8.6 Hz, 2H),1.52 (d, J=6.9 Hz, 3H). ESMS (M+1)=392.18.

Compound 280:(7S)-4,7,8-trimethyl-2-((cis-3-((3,4,5-trimethoxyphenoxy)methyl)-cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 3,4,5-timethoxyphenol to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 6.22 (s, 2H), 4.45-4.33 (m, 1H), 4.28 (q, J=6.9 Hz, 1H),3.94 (d, J=5.3 Hz, 2H), 3.80 (s, 6H), 3.68 (s, 3H), 3.24 (s, 3H),2.68-2.46 (m, 3H), 2.29 (s, 3H), 1.98 (dd, J=17.0, 8.0 Hz, 2H), 1.52 (d,J=6.9 Hz, 3H). ESMS (M+1)=458.17.

Compound 279.(7S)-2-((cis-3-((4-fluoro-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 4-fluoro-1H-pyrazole to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 7.63 (d, J=4.4 Hz, 1H), 7.35 (d, J=4.0 Hz, 1H), 4.38-4.22(m, 3H), 4.19-4.14 (m, 1H), 4.11 (d, J=5.9 Hz, 2H), 3.22 (s, 3H),2.61-2.39 (m, 4H), 2.29 (s, 3H), 1.96-1.73 (m, 3H), 1.51 (d, J=6.9 Hz,3H); ESMS (M+1)=360.17.

Compound 286:(7S)-2-((cis-3-(((4-fluorobenzyl)oxy)methyl)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-157 to provide the title product, 21.5% yield.1H NMR (300 MHz, CDCl₃) δ 7.49 (s, 1H), 7.37-7.24 (m, 2H), 7.11-6.98 (m,2H), 4.79 (d, J=7.8 Hz, 1H), 4.32 (q, J=8.1 Hz, 1H), 4.07 (q, J=6.8 Hz,1H), 3.44 (d, J=6.1 Hz, 2H), 3.05 (s, 3H), 2.55 (qd, J=7.5, 3.8 Hz, 2H),2.37-2.24 (m, 1H), 2.19 (s, 3H), 1.64 (dt, J=16.3, 5.3 Hz, 2H), 1.40 (d,J=6.8 Hz, 3H); ESMS (M+1)=400.28.

Compound 288:(7S)-2-((cis-3-(((4-fluorobenzyl)oxy)methyl)cyclobutyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-1 and B-157 to provide the title product, 55% yield. 1HNMR (300 MHz, CDCl₃) δ 7.43-7.25 (m, 5H), 7.10-6.98 (m, 2H), 4.49 (s,2H), 4.29 (q, J=8.0, 7.6 Hz, 1H), 4.09 (q, J=6.8 Hz, 1H), 3.47 (d, J=6.2Hz, 2H), 3.08 (s, 3H), 2.64-2.49 (m, 2H), 2.41-2.24 (m, 1H), 1.71 (p,J=8.9 Hz, 2H), 1.45 (d, J=6.9 Hz, 3H); ESMS (M+1)=386.41.

2M. Preparation of Compounds of Table 14

TABLE 14 Compound # R₁ R₆ R₅ Method 254 H Me

A 255 Me Me

B 256 H H

A 265 H H

A 289 H H

A 264 H Me

A 266 Me Me

B 290 H Me

A

Compound 254:(7S)-4,7,8-trimethyl-2-((trans-3-((3,4,5-trifluorobenzyl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-202 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.05-6.91 (m, 2H), 4.56-4.42 (m, 1H), 4.40-4.31 (m, 3H),4.31-4.16 (m, 2H), 4.09 (q, J=6.9 Hz, 1H), 3.05 (s, 3H), 2.56-2.40 (m,2H), 2.33-2.13 (m, 5H), 2.13-1.98 (m, 1H), 1.41 (d, J=6.9 Hz, 3H); ESMS(M+1)=422.34.

Compound 255:(7S)-4,5,7,8-tetramethyl-2-((trans-3-((3,4,5-trifluorobenzyl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-202 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.05-6.93 (m, 2H), 4.91 (d, J=6.2 Hz, 1H), 4.57-4.44 (m,1H), 4.40-4.31 (m, 2H), 4.24 (ddd, J=6.8, 5.7, 3.4 Hz, 1H), 4.01 (q,J=6.9 Hz, 1H), 3.30 (s, 3H), 3.01 (s, 3H), 2.56-2.41 (m, 2H), 2.35 (s,3H), 2.22 (ddt, J=12.8, 7.1, 3.8 Hz, 2H), 1.21 (d, J=6.9 Hz, 3H); ESMS(M+1)=436.34.

Compound 256:(7S)-7,8-dimethyl-2-((trans-3-((3,4,5-trifluorobenzyl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-1 and B-202 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.39 (s, 1H), 7.06-6.94 (m, 2H), 4.55-4.41 (m, 1H),4.41-4.20 (m, 3H), 4.11 (q, J=6.8 Hz, 1H), 3.09 (s, 3H), 2.56-2.39 (m,2H), 2.40-2.23 (m, 2H), 1.48 (d, J=6.9 Hz, 3H); ESMS (M+1)=408.3.

Compound 265:(7S)-2-((trans-3-((3,4-difluorobenzyl)oxy)cyclobutyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-1 and B-201 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.38 (d, J=3.0 Hz, 1H), 7.28-7.01 (m, 3H), 4.48 (td,J=7.9, 5.8 Hz, 1H), 4.46-4.36 (m, 2H), 4.29 (ddd, J=8.6, 6.9, 4.5 Hz,1H), 4.11 (dd, J=6.9, 1.3 Hz, 1H), 3.09 (s, 3H), 2.55-2.40 (m, 2H),2.39-2.24 (m, 2H), 1.48 (d, J=6.8 Hz, 3H); ESMS (M+1)=390.29.

Compound 289:(S)-7,8-dimethyl-2-((cis-3-methyl-3-((3,4,5-trifluorobenzyl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-1 and B-203 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.32 (s, 1H), 6.96-6.85 (m, 2H), 4.25 (dd, J=13.2, 1.1 Hz,3H), 4.01 (q, J=8.9, 7.9 Hz, 2H), 3.64-3.56 (m, 1H), 2.99 (s, 3H),2.97-2.80 (m, 1H), 2.43 (tt, J=9.3, 2.8 Hz, 2H), 2.26 (ddt, J=9.1, 7.1,2.3 Hz, 1H), 2.06 (q, J=9.4 Hz, 2H), 1.86-1.73 (m, 1H), 1.37 (t, J=3.5Hz, 5H), 1.28 (d, J=0.9 Hz, 1H); ESMS (M+1)=422.37.

Compound 264:(7S)-2-((trans-3-((3,4-difluorobenzyl)oxy)cyclobutyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-201 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.82 (s, 1H), 7.24-7.02 (m, 3H), 4.88 (d, J=6.2 Hz, 1H),4.55-4.33 (m, 3H), 4.31-4.17 (m, 1H), 4.08 (q, J=6.9 Hz, 1H), 3.05 (d,J=1.0 Hz, 3H), 2.57-2.40 (m, 2H), 2.33-1.96 (m, 5H), 1.41 (dd, J=6.8,1.0 Hz, 3H); ESMS (M+1)=404.33.

Compound 266:(7S)-2-((trans-3-((3,4-difluorobenzyl)oxy)-cyclobutyl)amino)-4,5,7,8-tetramethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-201 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 7.27-7.03 (m, 3H), 4.51 (t, J=6.7 Hz, 1H), 4.43-4.18 (m,3H), 4.01 (q, J=6.8 Hz, 1H), 3.30 (s, 3H), 3.01 (s, 3H), 2.55-2.41 (m,2H), 2.36 (s, 3H), 2.30-2.16 (m, 2H), 1.21 (d, J=6.9 Hz, 3H); ESMS(M+1)=418.39.

Compound 290:(7S)-4,7,8-trimethyl-2-((cis-3-methyl-3-((3,4,5-trifluorobenzyl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-203 to provide the title product. ESMS(M+1)=436.41.

Compound 376 and 377(7S)-4,7,8-trimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((1S,3S)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

The compounds were prepared by procedure Method B via reaction of A-2and B-142 to provide the title product as a mixture of transdiastereomers (Compound 375). The trans diastereomers were separated bySFC (Column: Chiralpak IB, 10×250 mm; 20% methanol (0.2%diethylamine)/800% CO₂, isocratic, flow rate: 10 ml/min) to provide theindividual diastereomers that were arbitrarily assigned:

Peak A: Rt 0.604 mins. (88% ee); 1H NMR (300 MHz, CDCl₃) δ 8.35 (d,J=2.8 Hz, 1H), 7.61 (s, 1H), 7.31-7.19 (m, 1H), 4.94 (tt, J=5.8, 2.7 Hz,1H), 4.79 (d, J=6.6 Hz, 1H), 4.48 (q, J=6.8 Hz, 1H), 4.06 (q, J=6.8 Hz,1H), 3.00 (s, 3H), 2.47-2.26 (m, 3H), 2.24 (s, 3H), 2.01-1.84 (m, 2H),1.70-1.55 (m, 1H), 1.39 (d, J=6.9 Hz, 3H). ESMS (M+1)=437.29.

Peak B: Rt 0.963 mins. (89.2% ee) 1H NMR (300 MHz, CDCl₃) δ 8.35 (d,J=2.8 Hz, 1H), 7.62 (s, 1H), 7.31-7.20 (m, 1H), 4.94 (dq, J=5.9, 2.9 Hz,1H), 4.78 (d, J=6.6 Hz, 1H), 4.48 (q, J=6.8 Hz, 1H), 4.06 (q, J=6.8 Hz,1H), 3.01 (s, 3H), 2.48-2.20 (m, 6H), 2.03-1.85 (m, 2H), 1.62 (ddd,J=13.4, 7.4, 4.3 Hz, 1H), 1.39 (d, J=6.8 Hz, 3H). ESMS (M+1)=437.29.

Compound 259:(7S)-4,7,8-trimethyl-2-((cis-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and B-143 to provide the title compound as a mixture oftrans diastereomers, 46% yield. 1H NMR (300 MHz, Methanol-d4) δ6.85-6.71 (m, 2H), 4.57-4.45 (m, 1H), 4.32 (q, J=6.8 Hz, 1H), 3.27 (s,3H), 2.60-2.42 (m, 1H), 2.33 (s, 3H), 2.28-2.15 (m, 1H), 2.11-2.00 (m,2H), 1.98-1.82 (m, 2H), 1.54 (d, J=6.9 Hz, 3H).

Compound 260:(7S)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and B-141 to provide the title compound as a mixture oftrans diastereomers, 55% yield. The diastereomer were separated bychiral HPLC (Chiralpak IF column, 4.6×250 mm; 15% ethanol/15%methanol/70% hexanes (0.2% diethylamine), isocratic) to provide eachindividual trans-diastereomer:

Compound 267:(S)-4,7,8-trimethyl-2-(((1R,3R)-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

Peak A: Rt 6.57 mins.; 99% ee. 1H NMR (300 MHz, CDCl₃) δ 9.14 (s, 1H),6.48-6.26 (m, 2H), 4.71 (t, J=8.5 Hz, 1H), 4.65 (td, J=5.9, 2.8 Hz, 1H),4.45-4.30 (m, 1H), 4.02 (dq, J=17.9, 6.9 Hz, 1H), 2.37-2.20 (m, 2H),2.16 (s, 3H), 2.14-2.04 (m, 1H), 1.88-1.68 (m, 2H), 1.59-1.39 (m, 1H),1.31 (dd, J=6.8, 2.3 Hz, 3H); ESMS (M+1)=422.34.

Compound 268:(S)-4,7,8-trimethyl-2-(((1S,3S)-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

Peak B: Rt 10.219 mins.; 99% ee. 1H NMR (300 MHz, CDCl₃) δ 9.04 (s, 1H),6.49-6.29 (m, 2H), 4.71 (t, J=10.2 Hz, 1H), 4.65 (td, J=5.9, 2.8 Hz,1H), 4.49-4.25 (m, 1H), 4.13-3.90 (m, 2H), 2.23 (ddd, J=15.1, 10.6, 5.2Hz, 2H), 2.15 (d, J=4.9 Hz, 4H), 2.11 (dd, J=14.6, 6.3 Hz, 1H),1.89-1.68 (m, 2H), 1.59-1.42 (m, 1H), 1.32 (d, J=6.8 Hz, 3H); ESMS(M+1)=422.38.

Compound 269:(7S)-4,5,7,8-tetramethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediates A-3 and B-141 to provide the title compound as a mixtureof trans diastereomers. 1H NMR (300 MHz, Methanol-d4) δ 6.77-6.65 (m,2H), 4.94 (d, J=1.9 Hz, 1H), 4.61-4.48 (m, 1H), 4.32 (q, J=6.9 Hz, 1H),3.34 (d, J=5.1 Hz, 3H), 3.23 (s, 3H), 2.52 (s, 3H), 2.42-2.20 (m, 4H),2.06 (ddd, J=20.5, 13.7, 6.8 Hz, 1H), 1.97-1.65 (m, 2H), 1.39 (dd,J=6.9, 1.3 Hz, 3H); ESMS (M+1)=404.29. The diastereomers were separatedby SFC (AD-H, 4.6×100 mm column, 10% methanol (0.2% diethylamine)/90%CO₂, Isocratic) to provide each individual trans diastereomers.

Compound 272:(S)-4,5,7,8-tetramethyl-2-(((1R,3R)-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

Peak A: Rt 0.488 mins.; 99.2% de. 1H NMR (300 MHz, CDCl₃) δ 6.54-6.39(m, 2H), 4.80-4.65 (m, 2H), 4.45 (dd, J=14.0, 7.0 Hz, 1H), 4.00 (q,J=6.9 Hz, 1H), 3.29 (s, 3H), 2.99 (s, 3H), 2.44-2.10 (m, 6H), 1.95-1.76(m, 2H), 1.57 (ddd, J=10.8, 7.7, 5.9 Hz, 1H), 1.20 (d, J=6.9 Hz, 3H);ESMS (M+1)=436.31.

Compound 273:(S)-4,5,7,8-tetramethyl-2-(((1S,3S)-3-(3,4,5-trifluorophenoxy)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

Peak B: Rt 0.553 mins.; 96.8% de. 1H NMR (300 MHz, CDCl₃) δ 6.49-6.30(m, 2H), 4.66 (ddd, J=20.7, 15.2, 10.6 Hz, 2H), 4.46-4.28 (m, 1H), 3.93(q, J=6.9 Hz, 1H), 3.21 (s, 3H), 2.91 (s, 3H), 2.26 (s, 3H), 2.25-1.99(m, 4H), 1.79 (ddd, J=21.3, 8.4, 4.2 Hz, 2H), 1.59-1.41 (m, 1H), 1.11(d, J=6.6 Hz, 3H); ESMS (M+1)=436.29.

Compound 57:(7S)-2-(((6-((4-fluorobenzyl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by general procedure Method A via reaction ofintermediates A-2 and B-144 to provide the title product. 1H NMR (400MHz, CDCl₃) δ 8.19-8.07 (m, 1H), 7.72-7.58 (m, 1H), 7.43 (q, J=5.2 Hz,2H), 7.06 (t, J=9.0 Hz, 2H), 6.86-6.65 (m, 1H), 5.32 (q, J=3.9, 2.9 Hz,2H), 4.49 (q, J=6.8, 3.6 Hz, 2H), 4.07 (q, J=6.1 Hz, 1H), 3.04 (d, J=3.0Hz, 3H), 2.30-2.11 (m, 3H), 1.39 (dd, J=7.5, 3.7 Hz, 3H). ESMS(M+1)=423.26.

Compound 70:(S)-2-(((5-((4-fluorobenzyl)oxy)pyridin-2-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via a reaction withintermediate A-2 and B-145 to provide the title product. 1H NMR (300MHz, CDCl₃) δ 9.09 (s, 1H), 8.29 (dd, J=2.9, 0.7 Hz, 1H), 7.39 (dd,J=8.5, 5.4 Hz, 2H), 7.31-7.23 (m, 1H), 7.19 (dd, J=8.6, 2.8 Hz, 1H),7.07 (t, J=8.6 Hz, 2H), 5.62 (t, J=5.7 Hz, 1H), 5.04 (s, 2H), 4.65 (dd,J=5.8, 4.1 Hz, 2H), 4.04 (q, J=6.9 Hz, 1H), 2.99 (s, 4H), 2.25 (s, 3H),1.38 (d, J=6.8 Hz, 3H); ESMS (M+1)=423.12.

Compound 54:(7S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediate A-2 and(6-(4-fluorophenoxy)pyridin-3-yl)methanamine via Method B procedure toprovide the title product. 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H),8.37-8.16 (m, 1H), 7.27 (dt, J=15.3, 8.1 Hz, 4H), 7.17-6.98 (m, 1H),4.72 (s, 2H), 4.31 (d, J=5.8 Hz, 1H), 3.21 (s, 3H), 2.33 (s, 3H),1.63-1.39 (m, 3H); ESMS (M+1)=409.13.

Compound 56:(7S)-2-(((6-(4-fluorophenoxy)pyridin-3-yl)methyl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of intermediate A-1 and(6-(4-fluorophenoxy)pyridin-3-yl)methanamine via procedure Method B toprovide the title product. 1H NMR (300 MHz, Methanol-d4) δ 8.16 (d,J=2.4 Hz, 1H), 7.87 (dd, J=8.5, 2.5 Hz, 1H), 7.18-7.05 (m, 4H), 6.94 (d,J=8.5 Hz, 1H), 4.60 (s, 2H), 4.32 (q, J=6.9 Hz, 1H), 3.23 (s, 3H), 1.56(d, J=6.9 Hz, 3H); ESMS (M+1)=395.22.

Compound 143:(S)-4,7,8-trimethyl-2-(((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure A via reaction of intermediatesA-2 and B-148 to provide the title product. 1H NMR (300 MHz,Methanol-d4) δ 8.95 (s, 1H), 8.47 (s, 1H), 8.08-7.89 (m, 3H), 4.58 (s,2H), 4.05 (q, J=6.8 Hz, 1H), 3.01 (s, 3H), 2.18 (s, 3H), 1.31 (d, J=6.8Hz, 3H); ESMS (M+1)=433.35

Compound 371:(7S)-2-(((S)-1-benzylpyrrolidin-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and (S)-1-benzylpyrrolidin-3-amine to provide the titleproduct. 1H NMR (400 MHz, Methanol-d4) δ 7.40-7.16 (m, 5H), 4.50-4.39(m, 1H), 4.06 (q, J=6.8 Hz, 1H), 3.64 (s, 2H), 3.03 (s, 3H), 2.94 (dd,J=9.8, 7.0 Hz, 1H), 2.73 (dd, J=14.8, 8.7 Hz, 1H), 2.57 (dd, J=15.7, 8.2Hz, 1H), 2.47 (dd, J=9.9, 5.1 Hz, 1H), 2.32 (ddd, J=14.0, 8.6, 5.7 Hz,1H), 2.16 (s, 3H), 1.67 (ddd, J=13.4, 8.3, 5.8 Hz, 1H), 1.31 (d, J=6.8Hz, 3H); ESMS (M+1)=367.33.

Compound 372:(7S)-2-(((R)-1-benzylpyrrolidin-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and (R)-1-benzylpyrrolidin-3-amine to provide the titleproduct. 1H NMR (400 MHz, Methanol-d4) δ 7.38-7.20 (m, 5H), 4.44 (ddt,J=10.0, 6.9, 5.1 Hz, 1H), 4.05 (q, J=6.8 Hz, 1H), 3.64 (s, 2H), 3.03 (s,3H), 2.93 (dd, J=9.9, 7.0 Hz, 1H), 2.78-2.68 (m, 1H), 2.57 (dd, J=15.4,8.3 Hz, 1H), 2.46 (dd, J=9.9, 5.0 Hz, 1H), 2.38-2.26 (m, 1H), 2.16 (s,3H), 1.68 (ddd, J=13.3, 8.2, 6.1 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H). ESMS(M+1)=367.33.

Compound 374:(7S)-2-(((S)-1-(4-fluorobenzyl)pyrrolidin-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and (S)-1-(4-fluorobenzyl)pyrrolidin-3-amine to providethe title product. 1H NMR (300 MHz, Methanol-d4) δ 7.35 (s, 2H), 7.04(dd, J=8.3, 7.2 Hz, 2H), 4.44 (s, 1H), 4.13-3.99 (m, 1H), 3.61 (s, 2H),3.02 (d, J=0.8 Hz, 3H), 2.91 (s, 1H), 2.71 (d, J=6.1 Hz, 1H), 2.60-2.37(m, 2H), 2.27 (d, J=13.6 Hz, 1H), 2.15 (d, J=1.6 Hz, 3H), 1.67 (s, 1H),1.31 (dd, J=6.6, 1.7 Hz, 3H); ESMS (M+1)=385.27.

Compound 278:(7S)-4,7,8-trimethyl-2-((2-(phenoxymethyl)cyclopropyl)-amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and 2-(phenoxymethyl)cyclopropan-1-amine to provide thetitle product. 1H NMR (300 MHz, Methanol-d4) δ 7.37-7.20 (m, 2H), 6.97(d, J=6.6 Hz, 3H), 4.30 (q, J=6.9 Hz, 1H), 4.22-4.12 (m, 1H), 3.89-3.74(m, 1H), 3.24 (d, J=1.4 Hz, 3H), 2.86-2.73 (m, 1H), 2.34 (s, 2H), 1.53(dd, J=6.9, 1.2 Hz, 3H), 1.06 (dd, J=13.1, 5.3 Hz, 2H); ESMS(M+1)=354.37.

2N. Preparation of Compounds 401, 402, 404-408

Compound 405:(7S)—N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-N-(4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)acetamide

To a solution of(7R)-4,7,8-trimethyl-2-[[1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazol-4-yl]methylamino]-5,7-dihydropteridin-6-one(250 mg, 0.5600 mmol) in anhydrous THE (3.750 mL) was added acetylacetate (87 mg, 80 μL, 0.8400 mmol) and DIEA (217 mg, 290 μL, 1.680mmol), the mixture was sealed in a microwave tube and heated at 100° C.for 24 hrs in a heating bath. The solvent was removed by evaporation,the residue was purified by silica gel column (40 g) in ISCO elutingwith DCM, 20% MeOH/DCM. The desired fractions were collected andevaporated. The resulting material was dried over 50° C. vacuum for overnight. chiral HPLC (Column: ChiralPak IC,), ee>99.9% (206.0 mg, 74.55%yield) 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.66-8.52 (m, 1H),7.94-7.77 (m, 2H), 7.74 (d, J=0.8 Hz, 1H), 7.35 (d, J=0.7 Hz, 1H), 5.42(s, 2H), 4.93-4.80 (m, 2H), 4.17 (q, J=6.8 Hz, 1H), 2.98 (s, 3H), 2.28(s, 3H), 2.24 (s, 3H), 1.26 (d, J=6.8 Hz, 3H). ESMS (M+1) 489.3.

Compound 408:1-((((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)((7S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)carbamoyl)oxy)ethylisobutyrate

To a solution of(7S)-4,7,8-trimethyl-2-[[1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazol-4-yl]methylamino]-5,7-dihydropteridin-6-one(200 mg, 0.4480 mmol) in anhydrous THE (2 mL) was added1-(4-nitrophenoxy)carbonyloxyethyl 2-methylpropanoate (161.4 mg, 0.5376mmol) and DIEA (2 eq); the mixture was sealed in a microwave tube andheated in heating bath at 110° C. for 24 hrs. UPLC showed desired Mw wasfound, evaporated the solvent, the residue was purified by columnchromatography (SiO₂) eluting with a gradient of dichloromethane to 20%methanol in dichloromethane. The desired fractions were collected andevaporated, the pure product was dried on vacuum for overnight toprovide the title product. (232.5 mg, 0.3816 mmol, 85.16%) 1H NMR (300MHz, DMSO-d6) δ 8.58 (d, J=1.2 Hz, 1H), 7.97-7.72 (m, 3H), 7.40 (s, 1H),6.74 (qd, J=5.5, 1.6 Hz, 1H), 5.45 (s, 2H), 4.87-4.61 (m, 2H), 4.16 (q,J=6.8 Hz, 1H), 2.96 (s, 3H), 2.51-2.39 (m, 1H), 2.26 (s, 3H), 1.39 (d,J=5.5 Hz, 3H), 1.31-1.21 (m, 3H), 1.09-0.96 (m, 6H). ESMS (M+1)=605.41.

General Procedures for Preparation of Compounds 406 and 402

tert-butyl(7S)-(2-oxo-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)(4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)ethyl)carbamate

To the solution of(S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(180 mg, 0.4032 mmol) and DIPEA (140 μL, 0.8038 mmol) in THE was added(4-nitrophenyl) 2-(tert-butoxycarbonylamino)acetate and DIPEA (140 μL,0.8038 mmol). After microwaved at 130° C. for 2 h, LCMS indicateddesired product. After concentration, the product was purified by silicagel chromatography to give the product (185 mg, 0.3037 mmol, 75.32%) 1HNMR (300 MHz, CDCl₃) δ 8.55 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 7.76-7.61(m, 2H), 7.58 (d, J=6.0 Hz, 2H), 5.50 (t, J=5.1 Hz, 1H), 5.33 (d, J=5.9Hz, 3H), 5.10 (s, 2H), 4.57-4.34 (m, 2H), 4.19 (q, J=6.8 Hz, 1H), 3.13(s, 3H), 2.36 (s, 3H), 1.48 (d, J=6.9 Hz, 3H), 1.45 (s, 9H). ESMS(M+1)=604.37.

Compound 406:(7S)-2-amino-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-N-(4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)acetamide

To a solution of tert-butyl(S)-(2-oxo-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)(4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)ethyl)carbamate(173 mg, 0.2840 mmol) in MeOH (0.5 mL) was added HCl (1 mL of 4 M, 4.000mmol) in dioxane (1 mL). The reaction was stirred for 1 h at RT. LCMSindicated completion of reaction. Removed the solvent, the product wastriturated by ether. (160 mg, 0.2740 mmol, 96.47%) 1H NMR (300 MHz,Methanol-d4) δ 8.45 (s, 1H), 7.98 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.77(d, J=8.1 Hz, 1H), 7.63 (d, J=4.8 Hz, 1H), 5.57-5.35 (m, 3H), 5.16 (d,J=3.3 Hz, 2H), 4.35 (d, J=18.0 Hz, 3H), 3.64 (q, J=1.2 Hz, 2H), 3.19 (d,J=3.5 Hz, 3H), 2.51-2.34 (m, 3H), 1.52 (t, J=6.7 Hz, 3H). ESMS(M+1)=504.38.

Compound 402:(S)-2-amino-3-methyl-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-N—((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)butanamide

Prepared in a similar manner as described above to give product HClsalt. (41 mg, 0.06629 mmol, 67.94% yield) 1H NMR (300 MHz, Methanol-d4)δ 8.49-8.32 (m, 1H), 7.81 (d, J=2.7 Hz, 2H), 7.76 (d, J=8.1 Hz, 1H),7.59 (s, 1H), 5.45 (s, 2H), 5.19-5.00 (m, 3H), 4.25 (q, J=6.8 Hz, 1H),3.14 (d, J=2.3 Hz, 3H), 2.36 (s, 3H), 2.04 (dt, J=12.7, 7.0 Hz, 1H),1.42 (dd, J=6.9, 4.3 Hz, 3H), 0.87 (d, J=6.9 Hz, 3H), 0.77 (d, J=6.8 Hz,3H). ESMS (M+1)=546.25.

Compound 407: methyl(7S)-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)(4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)carbamate

At 0° C., methyl carbonochloridate (158.8 mg, 129.8 μL, 1.680 mmol) wasadded dropwise to the solution of(S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(500 mg, 1.120 mmol) and DIPEA (361.9 mg, 487.7 μL, 2.800 mmol) in THF.After stirred over the weekend and reaction went to completion. Afterconcentration, the crude product was purified by silica gelchromatography to give the product (10% yield). 1H NMR (300 MHz, CDCl₃)δ 8.83 (s, 1H), 8.54 (s, 1H), 7.75-7.60 (m, 2H), 7.54 (d, J=9.0 Hz, 2H),5.33 (d, J=9.6 Hz, 2H), 5.04-4.72 (m, 2H), 4.16 (q, J=6.9 Hz, 1H), 3.79(s, 3H), 3.07 (s, 3H), 2.36 (s, 3H), 1.45 (d, J=6.9 Hz, 3H). ESMS(M+1)=505.33.

Compounds 401 and 404

These compounds were prepared similarly as described above for Compounds402, 406, 407 and 408

Compound 401:(7S)-3-cyclohexyl-1-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-1-(4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)urea

1H NMR (300 MHz, Methanol-d4) δ 8.52 (d, J=1.7 Hz, 1H), 7.87-7.67 (m,3H), 7.57 (s, 1H), 5.45 (s, 2H), 5.19 (s, 2H), 4.19 (q, J=6.8 Hz, 1H),3.79-3.62 (m, 1H), 3.11 (s, 3H), 2.32 (s, 3H), 1.95 (d, J=12.0 Hz, 2H),1.84-1.68 (m, 2H), 1.61 (s, 2H), 1.54-1.20 (m, 6H); ESMS (M+1)=572.32.

Compound 404:(7S)-6-acetamido-2-amino-N-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)-N—((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)hexanamide

1H NMR (300 MHz, Methanol-d4) δ 8.38 (d, J=4.3 Hz, 1H), 7.97 (s, 1H),7.85 (d, J=8.3 Hz, 1H), 7.72 (dt, J=8.2, 4.8 Hz, 1H), 7.59 (d, J=5.7 Hz,1H), 5.44 (s, 2H), 4.72-4.45 (m, 1H), 4.33 (t, J=6.3 Hz, 1H), 3.61 (m,2H), 3.15 (d, J=3.4 Hz, 3H), 3.09 (s, 2H), 2.41 (d, J=2.3 Hz, 3H),2.10-1.87 (m, 3H), 1.88-1.59 (m, 2H), 1.50 (dd, J=6.9, 2.8 Hz, 3H), 1.33(d, J=22.9 Hz, 4H); ESMS (M+1)=617.51.

2O. Preparation of Compounds 297, 299, 300, 301, 302, 306, 308, 309,316, 318, and 319

Compounds 308 & 309:(7S)-4,7,8-trimethyl-2-(((3S,5S)-5-((3,4,5-trifluorophenoxy)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((3R,5R)-5-((3,4,5-trifluorophenoxy)methyl)-tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

These compounds were prepared in 3 steps.

Step 1:(7S)-2-((cis-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

To a mixture of (7S)-2-chloro-4,7,8-trimethyl-5,7-dihydropteridin-6-one(191.1 mg, 0.8429 mmol),(cis)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-3-amine(333 mg, 0.8429 mmol) and tBuXPhos Pd G1 (23 mg, 0.03349 mmol) in tBuOH(5 mL) was added sodium t-butoxide (1.1 mL of 2 M, 2.11 mmol)) undernitrogen. The reaction was stirred at room temperature for 30 min. Water(50 ml) was added to the reaction and extracted with ethyl acetate (3×50ml). The combined organic extracts were dried over anhydrous sodiumsulfate, filtered and evaporated in vacuo. The resulting residue waspurified by column chromatography (SiO₂) eluting with a gradient of10-100% ethyl acetate in hexanes. The desired fractions were evaporatedto afford the title product as a mixture of cis isomers, wt. 282 mg (61%yield). 1H NMR (400 MHz, CDCl₃) δ 7.61-7.53 (m, 4H), 7.35-7.20 (m, 6H),4.81 (t, J=6.8 Hz, 1H), 4.47-4.36 (m, 1H), 3.99-3.82 (m, 3H), 3.67-3.53(m, 3H), 2.86 (s, 3H), 2.25 (dt, J=12.9, 7.7 Hz, 1H), 2.04 (d, J=3.1 Hz,3H), 1.68-1.56 (m, 1H), 1.25 (dd, J=6.9, 1.4 Hz, 3H), 0.95 (s, 9H). ESMS(M+1)=546.31.

Step 2:(7S)-2-((cis-5-(hydroxymethyl)tetrahydrofuran-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

To a solution of(7S)-2-((cis-5-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydrofuran-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(279 mg, 0.5045 mmol) in THE (6 mL) was added tetrabutylammoniumfluoride (757.4 μL of 1 M, 0.7574 mmol). The reaction was stirred atroom temperature for 12 hours. The reaction was evaporated in vacuo and20 ml of brine was added to the residue followed by extraction withethyl acetate (2×30 ml) and dichloromethane (2×10 ml). The combinedorganic extracts were dried over MgSO4, filtered, and evaporated. Thecrude product was purified by column chromatography (SiO₂) eluting witha gradient of d0-10% methanol in dichloromethane. The desired fractionswere evaporated in vacuo to afford the title product as a mixture of cisisomers, wt. 234 mg (92% yield). 1H NMR (400 MHz, CDCl₃) δ 5.65 (s, 1H),4.52 (d, J=4.0 Hz, 1H), 4.15-4.09 (m, 3H), 4.04 (dt, J=7.1, 3.5 Hz, 1H),3.93 (ddd, J=9.2, 5.2, 4.1 Hz, 1H), 3.86-3.74 (m, 3H), 3.59 (dd, J=11.8,4.7 Hz, 1H), 3.42-3.34 (m, 9H), 3.03 (s, 3H), 2.45-2.30 (m, 1H), 2.24(s, 3H), 1.75-1.62 (m, 10H), 1.38 (dd, J=6.8, 0.7 Hz, 4H), 1.27 (dt,J=14.3, 7.1 Hz, 9H), 1.00 (t, J=7.3 Hz, 13H). ESMS (M+1)=308.0.

Step 3: (Compounds 308 & 309).(7S)-4,7,8-trimethyl-2-(((3S,5S)-5-((3,4,5-trifluorophenoxy)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((3R,5R)-5-((3,4,5-trifluorophenoxy)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

To a solution of the cis diastereomers(7S)-2-[[(cis)-5-(hydroxymethyl)tetrahydrofuran-3-yl]amino]-4,7,8-trimethyl-5,7-dihydropteridin-6-one(150 mg, 0.3 mmol), 3,4,5-trifluorophenol (133 mg, 0.9 mmol) andtriphenylphosphine (196 mg, 0.75 mmol) in THE (4 mL) at room temperaturewas added diethyl azodicarboxylate (340 μL, 0.75 mmol). The reaction wasstirred at 50° C. for 12 hours. The reaction was evaporated in vacuo,and the residue purified by reverse phase chromatography to afford thetitle product, wt. 74 mg (48% yield); ESMS (M+1)=438.19.

The cis diastereomers were separated by SFC (Column: Chiralpak IC,10×250 mm; 40% methanol (0.2% diethylamine)/60% CO₂, isocratic, 10ml/min) and the cis isomers arbitrarily assigned.

Peak A: Rt 2.867 mins. (99% ee); 1H NMR (300 MHz, CDCl₃) δ 7.88 (s, 1H),6.71-6.52 (m, 2H), 5.31 (d, J=7.7 Hz, 1H), 4.54 (dd, J=7.2, 3.4 Hz, 1H),4.39-4.22 (m, 1H), 4.05 (dd, J=12.7, 5.6 Hz, 1H), 3.92-3.74 (m, 3H),2.99 (s, 3H), 2.51-2.33 (m, 1H), 2.15 (s, 3H), 1.76 (ddd, J=9.6, 5.3,3.8 Hz, 1H), 1.35 (t, J=8.5 Hz, 3H). ESMS (M+1)=438.14.

Peak B: Rt 3.773 mins. (99% ee); 1H NMR (300 MHz, CDCl₃) δ 8.00 (s, 1H),6.70-6.51 (m, 2H), 5.25 (d, J=8.0 Hz, 1H), 4.53 (ddt, J=11.7, 7.9, 3.8Hz, 1H), 4.38-4.19 (m, 1H), 4.10-4.01 (m, 1H), 3.88 (ddd, J=6.9, 5.2,1.8 Hz, 2H), 3.81 (dd, J=9.1, 2.7 Hz, 1H), 2.98 (s, 3H), 2.16 (s, 3H),1.75 (ddd, J=13.2, 5.4, 4.0 Hz, 1H), 1.33 (d, J=6.9 Hz, 3H). ESMS(M+1)=438.19.

Compound 306:(7S)-4,7,8-trimethyl-2-((cis-5-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

Diethyl azodicarboxylate (0.15 ml, 0.32 mmol) was added dropwise to asolution of(7S)-2-[[(cis)-5-(hydroxymethyl)tetrahydrofuran-3-yl]amino]-4,7,8-trimethyl-5,7-dihydropteridin-6-one(80 mg, 0.16 mmol), 3-(trifluoromethyl)-1H-pyrazole (65 mg, 0.48 mmol),and triphenylphosphine (84 mg, 0.32 mmol) in THE (2 ml). The reactionwas stirred at 50° C. for 12 hours then evaporated in vacuo. The crudeproduct was purified by preparative reverse phase HPLC (C18 column) toafford the title product as a mixture of cis diastereomers, wt 26 mg. 1HNMR (300 MHz, Methanol-d4) δ 7.80 (d, J=1.3 Hz, 1H), 6.59 (d, J=2.3 Hz,1H), 4.55-4.47 (m, 1H), 4.41 (dd, J=8.4, 3.8 Hz, 2H), 4.36-4.23 (m, 2H),4.01-3.91 (m, 1H), 3.89-3.80 (m, 1H), 3.24 (s, 3H), 2.52 (dt, J=7.0, 5.5Hz, 1H), 2.30 (s, 3H), 1.90-1.68 (m, 1H), 1.52 (d, J=6.9 Hz, 3H); ESMS(M+1)=426.26.

Compounds 301 and 302:(7S)-4,7,8-trimethyl-2-(((3R,5S)-5-((3,4,5-trifluorophenoxy)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((3R,5S)-5-((3,4,5-trifluorophenoxy)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

These compounds were prepared in 3 steps by the same method describedfor Compounds 308 and 309 via reaction of A-2 and(trans)-5-[[tert-butyl(diphenyl)silyl]-oxymethyl]tetrahydrofuran-3-amineas the initial reactants to provide a mixture of trans isomers (Compound299) that were separated by SFC (Column: Chiralpak IC, 10×250 mm; 40%ethanol (0.2% diethylamine)/60% CO₂, isocratic, 10 ml/min) to providethe trans isomers that were arbitrarily assigned.

Peak A: Rt 0.570 mins. (99% ee); 1H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H),6.55-6.41 (m, 2H), 4.97 (s, 1H), 4.57-4.45 (m, 1H), 4.38 (dt, J=7.9, 5.8Hz, 1H), 4.13 (dd, J=9.1, 5.5 Hz, 1H), 4.01 (q, J=6.9 Hz, 1H), 3.88(ddd, J=15.4, 9.8, 4.7 Hz, 2H), 3.65 (dd, J=9.1, 4.0 Hz, 1H), 2.98 (s,3H), 2.15 (s, 3H), 2.08-1.95 (m, 2H), 1.34 (d, J=6.9 Hz, 3H). ESMS(M+1)=438.19.

Peak B: Rt 0.856 mins. (99% ee); 1H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H),6.70 (s, 1H), 6.55-6.40 (m, 2H), 4.50 (d, J=5.2 Hz, 1H), 4.47-4.35 (m,1H), 4.21-4.10 (m, 1H), 4.08 (q, J=6.9 Hz, 1H), 3.94 (dd, J=10.0, 3.4Hz, 1H), 3.85 (dd, J=9.9, 5.2 Hz, 1H), 3.70 (dd, J=9.2, 4.3 Hz, 1H),3.06 (s, 3H), 2.27 (s, 3H), 2.20-2.02 (m, 2H), 1.43 (d, J=6.9 Hz, 3H).ESMS (M+1)=438.23.

Compound 297:(7S)-2-((trans-4-(4-fluorophenoxy)tetrahydrofuran-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-156 to provide the title product as a mixture oftrans isomers, 10% yield. 1H NMR-1H NMR (300 MHz, Methanol-d4) δ 6.98(ddd, J=13.7, 9.2, 3.4 Hz, 5H), 4.96-4.86 (m, 1H), 4.63 (s, 1H),4.33-4.15 (m, 3H), 4.01-3.78 (m, 2H), 3.05 (d, J=5.4 Hz, 3H), 2.31 (s,3H), 1.50 (dd, J=6.9, 2.0 Hz, 3H); ESMS (M+1)=388.22.

Compound 300, 316, 318, and 319:(7S)-4,7,8-trimethyl-2-(trans-(5-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-((trans-5-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)tetrahydrofuran-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by reaction of(7S)-2-((trans-5-(hydroxymethyl)tetrahydrofuran-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand 3-(trifluoromethyl)-1H-pyrazole under the Mitsunobu conditions runfor Compound 306 to afford a mixture of trans diastereomers as well asregioisomers (Compound 300) based on the 1H NMR. The mixture wasseparated by SFC (Chiralpak IC column (50% CO2/50% methanol (0.2%diethylamine), isocratic); 12 ml/min to afford

Peak A (Compound 318)

Rt 5.33 mins. (>99% ee); 1H NMR (400 MHz, CDCl₃) δ 7.57 (s, 1H), 7.51(s, 1H), 6.46 (d, J=2.1 Hz, 1H), 4.81 (s, 1H), 4.49-4.27 (m, 3H), 4.18(dd, J=14.2, 5.9 Hz, 1H), 4.03-3.93 (m, 2H), 3.59 (dd, J=9.1, 3.9 Hz,1H), 2.96 (d, J=8.9 Hz, 3H), 2.11 (s, 3H), 1.88 (dt, J=31.8, 13.1 Hz,1H), 1.33 (d, J=6.8 Hz, 3H); ESMS (M+1)=426.18.

Peak B (Compound 319)

Rt 7.15 mins. (>99% ee); 1H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=8.9 Hz,2H), 6.55 (d, J=1.3 Hz, 1H), 4.57-4.38 (m, 3H), 4.25 (ddd, J=19.1, 14.1,6.0 Hz, 3H), 3.61 (dd, J=9.3, 3.9 Hz, 2H), 2.97 (d, J=3.7 Hz, 3H), 2.11(d, J=4.6 Hz, 3H), 1.33 (d, J=6.9 Hz, 3H); ESMS (M+1)=426.14.

Peak C & D (Compound 316)

Rt 9.95 mins. (2 peaks observed, not separable); 1H NMR (400 MHz, CDCl₃)δ 7.73 (s, 1H), 7.49 (d, J=15.1 Hz, 1H), 6.51 (d, J=36.2 Hz, 1H), 4.76(s, 1H), 4.61-4.41 (m, 1H), 4.45-4.26 (m, 3H), 4.19 (td, J=13.1, 5.0 Hz,1H), 3.68-3.51 (m, 1H), 2.95 (d, J=4.7 Hz, 3H), 2.12 (s, 3H), 1.98-1.83(m, 3H), 1.32 (d, J=6.8 Hz, 3H); ESMS (M+1)=426.18.

2P. Preparation of Compounds

The following compounds were prepared in a similar manner as thosedescribed above for the compounds of Tables 1-14.

Compound 127:(7S)-2-(((1-((R)-1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-160 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.69 (s, 1H), 7.44 (s, 1H), 4.37 (s, 3H), 4.07 (q,J=6.8 Hz, 2H), 3.07 (s, 3H), 3.05-2.82 (m, 3H), 2.71 (td, J=8.5, 6.3 Hz,1H), 2.49-2.23 (m, 3H), 2.18 (s, 3H), 2.15-1.49 (m, 11H), 1.33 (d, J=6.8Hz, 3H); ESMS (M+1)=475.3.

Compound 142:(7S)-2-(((1-((S)-1-(4,4-difluorocyclohexyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-161 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.69 (s, 1H), 7.44 (s, 1H), 4.51-4.21 (m, 2H), 4.07(q, J=6.8 Hz, 1H), 3.39-3.21 (m, 2H), 3.12-2.77 (m, 6H), 2.69 (td,J=8.5, 6.4 Hz, 1H), 2.50-2.23 (m, 2H), 2.22-1.48 (m, 12H), 1.33 (d,J=6.8 Hz, 3H). ESMS (M+1)=475.24.

Compound 169:(7S)-2-(((6-((1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)pyridin-3-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates B-147 and A-2 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 8.14 (s, 1H), 7.68 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.5Hz, 2H), 6.72 (d, J=8.4 Hz, 1H), 6.52 (s, 2H), 5.59 (s, 1H), 4.50 (d,J=27.5 Hz, 3H), 4.06 (d, J=6.4 Hz, 1H), 3.65 (s, 1H), 3.48-3.32 (m, 5H),3.04 (s, 3H), 2.47-2.06 (m, 5H), 1.33 (d, J=6.5 Hz, 3H); ESMS(M+1)=478.45.

Compound 170:(7S)-2-(((1-((R)-1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-163 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.53 (d, J=35.2 Hz, 2H), 6.93 (s, 2H), 6.57 (s, 2H),5.49 (s, 1H), 5.05 (s, 1H), 4.36 (s, 2H), 4.04 (s, 1H), 3.83-3.39 (m,4H), 3.03 (s, 3H), 2.46 (d, J=34.0 Hz, 2H), 2.16 (s, 2H), 1.31 (s, 3H);ESMS (M+1)=451.48.

Compound 171:(7S)-2-(((1-((S)-1-(4-fluorophenyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-162 to provide the title product. 1H NMR (300MHz, Methanol-d4) δ 7.53 (d, J=35.2 Hz, 2H), 6.93 (s, 2H), 6.57 (s, 2H),5.49 (s, 1H), 5.05 (s, 1H), 4.36 (s, 2H), 4.04 (s, 1H), 3.83-3.39 (m,4H), 3.03 (s, 3H), 2.46 (d, J=34.0 Hz, 2H), 2.16 (s, 2H), 1.31 (s, 3H);ESMS (M+1)=451.48.

Compound 219:(7S)-2-(((1-(((S)-1-(3,5-difluorophenyl)pyrrolidin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediate A-2 and B-200 to provide the title product, 50 mg (22.6%yield) of title compound. 1H NMR (300 MHz, Methanol-d4) δ 7.79 (s, 1H),7.68 (s, 1H), 6.40 (ddd, J=11.3, 6.6, 2.1 Hz, 3H), 4.63 (s, 2H),4.58-4.30 (m, 4H), 3.75-3.43 (m, 3H), 2.49 (s, 3H), 2.42-2.03 (m, 4H),1.97-1.48 (m, 6H). ESMS (M+1)=483.44.

Compound 244:(7S)-2-((1-benzylazetidin-3-yl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-2 and 1-benzyl-3-aminoazetidine to provide the titleproduct. 1H NMR (300 MHz, CDCl₃) δ 7.41-7.24 (m, 5H), 4.52-4.42 (m, 1H),4.07-3.96 (m, 1H), 3.94-3.72 (m, 4H), 3.44-3.35 (m, 1H), 3.12-3.07 (m,3H), 2.91-2.79 (m, 2H), 2.28 (dd, J=7.6, 4.7 Hz, 2H), 1.43 (dd, J=6.9,3.9 Hz, 3H); ESMS (M+1)=353.33.

Compound 245:(7S)-2-((1-benzylazetidin-3-yl)amino)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method B via reaction ofintermediate A-1 and 1-benzyl-3-aminoazetidine to provide the titleproduct. 1H NMR (300 MHz, CDCl₃) δ 7.44-7.21 (m, 6H), 4.46 (ddd, J=11.1,7.6, 4.8 Hz, 1H), 4.10-3.79 (m, 4H), 3.68-3.47 (m, 1H), 3.47-3.23 (m,1H), 3.10 (s, 3H), 2.99-2.88 (m, 2H), 1.48 (dq, J=6.5, 3.7 Hz, 3H); ESMS(M+1)=339.33.

Compound 298:3,4,5-trifluoro-N-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclopentyl)benzamide

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-159 to provide the title product. ESMS(M+1)=449.28.

Compounds 310 and 311:(7S)-4,7,8-trimethyl-2-(((1S,3S)-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((1R,3R)-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by procedure Method A via reaction ofintermediates A-2 and B-158 to provide the title products as a mixtureof trans diastereomers. The diastereomers were separated by chiral HPLC(Chiralpak AD-H column; 85% hexanes/7.5% ethanol/7.5% methanol (0.2%diethylamine), isocratic, 20 ml/min) and arbitrarily assigned as Peak Aand B.

Peak A: Rt 6.486 mins. (>99% ee); 1H NMR (300 MHz, CDCl₃) δ 8.60 (s,1H), 7.48 (dq, J=1.9, 1.0 Hz, 1H), 6.55-6.47 (m, 1H), 4.94-4.70 (m, 2H),4.57 (q, J=6.5 Hz, 1H), 4.08 (q, J=6.9 Hz, 1H), 3.05 (s, 3H), 2.62-2.31(m, 3H), 2.28-2.05 (m, 5H), 1.65 (dddd, J=13.8, 9.0, 5.7, 2.4 Hz, 1H),1.41 (d, J=6.8 Hz, 3H); ESMS (M+1)=410.18.

Peak B: Rt 10.216 mins. (>99% ee); 1H NMR (300 MHz, CDCl₃) δ 8.45 (s,1H), 7.49 (dq, J=2.2, 1.0 Hz, 1H), 6.51 (dd, J=2.3, 0.7 Hz, 1H), 4.87(dt, J=12.9, 6.6 Hz, 2H), 4.63-4.50 (m, 1H), 4.08 (q, J=6.9 Hz, 1H),3.05 (s, 3H), 2.63-2.30 (m, 3H), 2.28-2.11 (m, 6H), 1.72-1.57 (m, 1H),1.41 (d, J=6.8 Hz, 3H). ESMS (M+1)=410.18

Preparation of Compound 409.(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

Step A: MethylN-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-valinate.

A flask with 2,4-Dichloro-6-methyl-5-nitropyrimidine (10 g, 48.1 mmol),methyl methyl-L-valinate hydrochloride (9.61 g, 53 mmol), and sodiumbicarbonate (20.2 g, 240.4 mmol) in cyclohexane (100 ml) was equippedwith a Dean Stark trap and heated to reflux. The hot reaction mixturewas filtered through Celite hot. The filtrate was evaporated in vacuo toafford the title product, wt. 15.5 g that was used without furtherpurification. 1H NMR (300 MHz, CDCl₃) δ 4.99 (d, J=10.5 Hz, 1H), 3.77(s, 3H), 2.95 (s, 3H), 2.49 (s, 3H), 2.45-2.23 (m, 1H), 1.10 (d, J=6.6Hz, 3H), 0.99 (d, J=6.7 Hz, 3H); ESMS (M+1)=317.04.

Step B: MethylN-(2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-valinate

Methyl N-(2-chloro-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-valinate(12 g, 37.9 mmol),(1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanamine (B-67;16.54 g, 49.3 mmol), and sodium bicarbonate (9.88 g, 118 mmol) weretaken into 120 ml of tetrahydrofuran and refluxed for 6 hours. Thereaction was filtered through Celite and the filtrated evaporated invacuo to afford a yellow oil. The cured product was filtered through asilica gel plug eluting with ethyl acetate. The collected fractions wereevaporated in vacuo to afford 19 g of the title product as a yellow oil.ESMS (M+1)=503.23.

Step C:(S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onehydrochloride

MethylN-(2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-6-methyl-5-nitropyrimidin-4-yl)-N-methyl-L-valinate(19 g, 37.9 mmol) was dissolved in 200 ml of methanol and 5% Pt/C (1.5g, 0.384 mmol) was added to the solution and the mixture placed on theParr shaker under 58 psi of hydrogen. After 5 hours, the reaction wasfiltered through Celite and the colorless filtrate evaporated in vacuoto afford the crude product. The crude product was purified by columnchromatography (SiO₂, 330 g) eluting with a gradient of dichloromethaneto 20% methanol in dichloromethane. The desired fractions were combinedand evaporated to provide the product as a white foam, wt. 13 g (77%yield). The product was dissolved in 100 ml of methanol and treated with1N HCl in diethyl ether (36 ml) and stirred for 30 minutes. The solventwas removed in vacuum and the resulting foam was triturated with 150 mlof t-butylmethyl ether and stirred for 30 minutes. The resultingmaterial was collected by vacuum filtration and the filter cake dried at50° C. overnight to provide the title product, wt. 13 g. [α]_(D)=+60.0°(c=1.0, MeOH). Chiral HPLC(Chiralpak IC column, 20% MeOH/30% EtOH/50%hexanes (0.1% diethylamine), isocratic): Rt 10.646 minutes (>98% ee). 1HNMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.53 (s, 1H), 8.31 (d, J=2.1Hz, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.70 (dd, J=8.2, 2.5 Hz, 1H), 7.50(d, J=8.2 Hz, 2H), 5.35 (s, 2H), 4.49-4.34 (m, 2H), 4.16 (d, J=3.8 Hz,1H), 3.18 (s, 3H), 2.35-2.10 (m, 4H), 1.01 (d, J=6.9 Hz, 3H), 0.77 (d,J=6.9 Hz, 3H). ESMS (M+1)=441.26.

2Q. Preparations of Compounds

Table 15 provides certain compounds prepared by Method A procedure byreaction of Intermediate A-# and B-52 (See procedure for compound 46),and ¹H NMR data are also provided for certain compounds.

TABLE 15 Com- Inter- Op pound mediate No. R³ R⁴ A-# rotation M + 1 436—C(CH₃)₃ H A-55 +54.6° 489.27 c = 0.5 CHCl₃ 495 —CH₂CF₃ H A-57 +18.24°515.28 c = 0.5 MeOH 498 —(R)—CH(OCH₃)CH₃ H A-59 +72.6° 491.32 c = 0.5MeOH 563 —CH₂CH(CH₃)₂ H A-60 80.4 489.52 c = 0.5 CHCl3 589 —CH₂CH₂OCH₃ HA-62 +87.0° 491.07 c = 1.0 MeOH 590 —CH₂OtBu H A-63 38.2 519.06 c = 0.5CHCl3 604 —CH₂OH H * 38.2 463.61 c = 0.5 CHCl3 600 Spiro-oxetan3-yl A-64475.26 601

A-65 509.25 661

H A-66 78.0 c = 0.5 MeOH 517.22 665

H A-68 61.0 c = 0.5 CHCl3 503.26 726 —C(CH₃)₂OH H A-61 +61.6 491.29 c =0.5 MeOH 742 (R)—CH(OtBu)CH₃ H A-74 142.2 533.46 c = 0.5 CHCl₃ 744(R)—CH(OH)CH₃ H ** 32.2 c = 0.5 CHCl₃ 703 —CH₂OCH₃ —CH₃ A-69 491.2 707—CH₃ —CH₂OCH₃ A-70 −43.3 491.25 c = 0.5 MeOH 662

A-67 +28.3° c = 1.0 MeOH 489.26 663

A-67 −27° c = 1.0 MeOH 489.22 * Compound 604 was prepared bydeprotection of Compound 590 in 4M HCl in dioxane and methanol at 65° C.** Compound 744 was prepared by deprotection of Compound 742 in asimilar manner.

Compound 436.(7S)-7-(tert-butyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.52 (d, J=1.7 Hz, 1H),7.63-7.52 (m, 2H), 7.48 (s, 1H), 7.37 (s, 1H), 5.28 (s, 2H), 5.20 (d,J=12.9 Hz, 1H), 4.37 (d, J=5.7 Hz, 2H), 3.62 (s, 1H), 3.13 (s, 3H), 2.15(s, 3H), 0.92 (s, 9H).

Compound 495.(S)-4,8-dimethyl-7-(2,2,2-trifluoroethyl)-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.62 (d, J=1.9 Hz, 1H),7.88-7.78 (m, 2H), 7.75 (s, 1H), 7.42 (s, 1H), 6.60 (t, J=6.0 Hz, 1H),5.44 (s, 2H), 4.40 (dd, J=6.0, 4.0 Hz, 1H), 4.23 (d, J=6.0 Hz, 2H), 2.99(s, 3H), 2.84-2.70 (m, 1H), 2.13 (s, 3H).

Compound 498.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.63 (s, 1H), 7.92-7.82 (m,2H), 7.76 (d, J=0.8 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 6.58 (t, J=6.0 Hz,1H), 5.44 (s, 2H), 4.24 (d, J=6.0 Hz, 2H), 3.92 (dd, J=5.9, 0.9 Hz, 1H),3.47 (p, J=6.2 Hz, 1H), 3.16 (s, 3H), 3.08 (s, 3H), 2.12 (s, 3H), 1.08(d, J=6.3 Hz, 3H).

Compound 563.(S)-7-isobutyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.87 (s, 1H), 7.75-7.62(m, 2H), 7.57 (d, J=0.7 Hz, 1H), 7.50-7.38 (m, 1H), 5.37 (s, 2H), 4.91(d, J=6.1 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 4.01 (dd, J=7.4, 5.9 Hz, 1H),3.07 (s, 3H), 2.22 (s, 3H), 1.80 (dp, J=12.9, 6.6 Hz, 1H), 1.61 (ddd,J=7.9, 5.6, 1.4 Hz, 2H), 0.99 (d, J=6.4 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H).

Compound 589.(S)-7-(2-methoxyethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 9.10 (s, 1H), 8.62-8.54 (m, 1H),7.71-7.61 (m, 1H), 7.55 (d, J=0.7 Hz, 1H), 7.42 (d, J=0.8 Hz, 1H), 5.33(d, J=17.3 Hz, 1H), 4.91 (t, J=5.9 Hz, 1H), 4.43 (d, J=5.8 Hz, 1H), 4.15(dd, J=7.3, 4.2 Hz, 1H), 3.42 (ddd, J=7.6, 5.6, 3.6 Hz, 1H), 3.21 (s,2H), 3.05 (s, 2H), 2.24 (s, 2H), 2.26-2.05 (m, 1H), 2.07-1.87 (m, OH).

Compound 590.(S)-7-(tert-butoxymethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.66-8.47 (m, 2H), 7.66 (d, J=1.4 Hz,2H), 7.56 (d, J=0.7 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 5.36 (s, 2H), 4.93(t, J=5.8 Hz, 1H), 4.44 (d, J=5.8 Hz, 2H), 4.08 (t, J=3.2 Hz, 1H), 3.70(dd, J=3.2, 2.0 Hz, 2H), 3.08 (s, 3H), 2.21 (s, 3H), 1.04 (d, J=1.1 Hz,9H).

Compound 604.(S)-7-(hydroxymethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.53 (s, 1H), 7.85-7.75 (m, 2H), 7.73(s, 1H), 7.54 (s, 1H), 5.45 (s, 2H), 4.41 (s, 2H), 4.06 (t, J=2.8 Hz,1H), 3.99-3.81 (m, 2H), 3.11 (s, 3H), 2.15 (s, 3H).

Compound 600.4′,8′-dimethyl-2′-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[oxetane-3,7′-pteridin]-6′-one

¹H NMR (400 MHz, Chloroform-d) δ 8.67-8.50 (m, 2H), 7.83-7.63 (m, 2H),7.58 (s, 1H), 7.44 (s, 1H), 5.38 (s, 2H), 5.30 (d, J=7.1 Hz, 2H), 4.92(t, J=6.5 Hz, 3H), 4.46 (d, J=5.8 Hz, 2H), 3.50 (s, 3H), 2.26 (s, 3H).

Compound 601.3,3-difluoro-4′,8′-dimethyl-2′-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-3-yl)methyl)amino)-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-pteridin]-6′-one

¹H NMR (300 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.59 (d, J=1.9 Hz, 1H),7.74-7.64 (m, 2H), 7.57 (d, J=0.7 Hz, 1H), 7.44 (d, J=0.8 Hz, 1H), 5.38(s, 2H), 4.97 (t, J=5.8 Hz, 1H), 4.45 (d, J=5.8 Hz, 2H), 3.62-3.38 (m,2H), 3.24 (s, 3H), 3.19-3.03 (m, 1H), 2.28 (s, 3H).

Compound 661.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO) δ 9.91 (s, 1H), 8.63 (s, 1H), 7.85 (dt, J=8.1,7.0 Hz, 2H), 7.74 (s, 1H), 7.42 (s, 1H), 6.49 (s, 1H), 5.44 (s, 2H),4.23 (d, J=6.0 Hz, 2H), 4.20 (s, 1H), 3.09 (s, 3H), 3.06 (s, 3H),2.27-2.17 (m, 1H), 2.17-2.05 (m, 5H), 2.01-1.91 (m, 1H), 1.77-1.63 (m,1H), 1.55 (dt, J=9.1, 8.0 Hz, 1H).

Compound 665.7-(1-methoxycyclopropyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 8.24 (s, 1H), 7.67 (d,J=1.5 Hz, 2H), 7.57 (d, J=2.0 Hz, 1H), 7.44 (s, 1H), 5.37 (s, 2H), 4.88(d, J=6.0 Hz, 1H), 4.46 (d, J=5.7 Hz, 2H), 3.70 (d, J=1.9 Hz, 1H), 3.19(d, J=1.8 Hz, 3H), 3.17 (d, J=1.9 Hz, 3H), 2.24 (d, J=1.8 Hz, 3H),1.13-0.87 (m, 3H), 0.86-0.72 (m, 1H)

Compound 726.(S)-7-(2-hydroxypropan-2-yl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.64 (s, 1H), 7.87 (d, J=7.4Hz, 1H), 7.83 (d, J=9.7 Hz, 1H), 7.76 (s, 1H), 7.43 (s, 1H), 6.52 (s,1H), 5.44 (s, 2H), 4.69 (s, 1H), 4.24 (d, J=6.1 Hz, 2H), 3.79 (s, 1H),3.19-3.09 (m, 3H), 2.09 (s, 3H), 1.16 (d, J=16.2 Hz, 3H), 0.89 (d,J=23.9 Hz, 3H).

Compound 742.(S)-7-((S)-1-(tert-butoxy)ethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.75-7.61 (m, 3H), 7.57(s, 1H), 7.43 (s, 1H), 5.37 (s, 2H), 4.84 (s, 1H), 4.46 (d, J=5.8 Hz,2H), 3.93 (t, J=6.0 Hz, 1H), 3.58-3.43 (m, 2H), 3.33-3.13 (m, 3H), 2.20(d, J=1.1 Hz, 3H), 1.36-1.20 (m, 3H), 1.15-0.96 (m, 9H).

Compound 744.(S)-7-((R)-1-hydroxyethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, Methanol-d₄) δ 8.59 (s, 1H), 7.93 (d, J=8.2 Hz, 2H),7.84 (d, J=8.4 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 5.55 (d, J=4.0 Hz, 2H),4.60 (d, J=2.0 Hz, 2H), 4.21 (dt, J=12.5, 3.4 Hz, 2H), 3.46-3.39 (m,3H), 2.33 (d, J=1.8 Hz, 3H), 1.36 (d, J=6.4 Hz, 3H).

Compound 703.7-(methoxymethyl)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.63 (s, 1H), 7.89-7.80 (m,2H), 7.75 (s, 1H), 7.45 (d, J=22.5 Hz, 1H), 6.49 (s, 1H), 5.44 (s, 2H),4.23 (d, J=6.0 Hz, 2H), 3.73-3.61 (m, 1H), 3.55 (t, J=12.0 Hz, 1H), 3.20(d, J=6.4 Hz, 3H), 2.97 (d, J=4.0 Hz, 3H), 2.15-2.05 (m, 3H), 1.32 (s,3H).

Compound 707.7-(methoxymethyl)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.63 (s, 1H), 7.86 (dt, J=9.8,8.1 Hz, 2H), 7.76 (s, 1H), 7.43 (s, 1H), 6.59 (s, 1H), 5.45 (s, 2H),4.24 (d, J=6.0 Hz, 2H), 3.66 (d, J=10.0 Hz, 1H), 3.55 (d, J=10.1 Hz,1H), 3.19 (s, 3H), 3.00 (d, J=15.7 Hz, 3H), 2.11 (s, 3H), 1.34 (s, 3H).

Compound 662.4′,8′-dimethyl-2′-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

¹H NMR (400 MHz, Chloroform-d) δ 8.44 (s, 1H), 7.52 (t, J=1.8 Hz, 2H),7.41 (s, 1H), 7.28 (s, 1H), 5.22 (s, 2H), 4.74 (t, J=5.8 Hz, 1H), 4.29(d, J=5.8 Hz, 2H), 4.12 (d, J=9.9 Hz, 1H), 4.05 (dd, J=8.5, 3.4 Hz, 1H),3.99 (s, OH), 3.73 (q, J=8.5 Hz, 1H), 3.29 (q, J=7.1 Hz, 1H), 2.96 (s,3H), 2.45 (ddd, J=13.4, 7.6, 3.4 Hz, 1H), 2.10 (s, 3H), 1.02 (dt,J=37.1, 7.1 Hz, 2H).

Compound 663.4′,8′-dimethyl-2′-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

¹H NMR (400 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.68 (t, J=1.9 Hz, 2H),7.57 (s, 1H), 7.43 (s, 1H), 5.38 (s, 2H), 4.86 (t, J=5.8 Hz, 1H), 4.45(d, J=5.7 Hz, 2H), 4.32-4.05 (m, 3H), 3.91 (q, J=8.5 Hz, 1H), 3.12 (d,J=1.5 Hz, 3H), 2.62 (ddd, J=13.5, 7.7, 3.6 Hz, 1H), 2.22 (d, J=1.7 Hz,3H), 1.34-1.21 (m, 2H).

Compound 497.(7S)-7-ethyl-8-isopropyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

Compound 497.(7S)-7-ethyl-8-isopropyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

was prepared by the general procedure for Method A (see Compound 46) viareaction of Intermediate A-76 and B-52 to afford the title product. 1HNMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.63 (s, 1H), 7.96-7.81 (m, 2H),7.76 (s, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 7.01 (s, 1H), 5.45 (s, 2H),4.43-4.20 (m, 3H), 4.11 (dd, J=6.7, 2.9 Hz, 1H), 1.88-1.54 (m, 2H),1.34-1.17 (m, 6H), 0.78 (t, J=7.4 Hz, 3H). ESI-MS m/z calc. 474.21033,found 475.37 (M+1)⁺; 473.37 (M−1)+; [α]D=+136.56° (c=1.0, MeOH). ChiralHPLC (IC column, 2×250 mm; 20% methanol/30% ethanol/50% hexanes (0.1%diethylamine)): Rt 8.2 mins. (97% ee).

Example 2R

Table 16 shows certain compounds prepared by Method A by reaction ofIntermediate A-# and B-89 (See procedure for compound 46). ¹H NMR datafor certain compounds are also provided.

TABLE 16 Compound No. R³ R⁴ Int. A-# [α]_(D) M + 1 656

H A-59 +74.7° c = 0.5 CHCl₃ 493.35 666

H A-68 +60.7° c = 0.5 CHCl₃ 506.27 670

H A-66 +95.8° c = 0.5 CHCl₃ 520.23 678 —CH₂CH₂OCH₃ H A-62 +90.3° 493.95c = 0.5 MeOH 704 —CH₂OCH₃ CH₃ A-69 494.26 709 —CH₃ CH₂OCH₃ A-70 −31.5494.31 c = 0.5 MeOH

Compound 656.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 7.52 (s, 1H), 7.47 (d, J=4.7 Hz, 1H),6.50 (s, 1H), 5.83 (s, 1H), 5.54 (s, 1H), 5.32 (d, J=3.9 Hz, 2H),4.41-4.20 (m, 2H), 3.84 (d, J=27.0 Hz, 4H), 3.47 (p, J=6.4 Hz, 1H), 3.23(d, J=7.1 Hz, 3H), 3.07 (s, 2H), 2.37 (s, 3H), 1.22 (dd, J=6.3, 3.6 Hz,3H).

Compound 666.7-(1-methoxycyclopropyl)-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.13 (s, 1H), 7.53 (d, J=2.0 Hz, 1H),7.34 (d, J=2.2 Hz, 1H), 6.51 (s, 1H), 5.32 (d, J=2.1 Hz, 2H), 4.84 (d,J=6.1 Hz, 1H), 4.52-4.35 (m, 2H), 3.87 (d, J=2.1 Hz, 3H), 3.70 (d, J=2.2Hz, 1H), 2.23 (d, J=2.2 Hz, 3H), 1.41-1.17 (m, 2H), 1.10-0.85 (m, 2H).

Compound 670.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ9.92 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H),6.57 (s, 1H), 6.51 (s, 1H), 5.44 (s, 2H), 4.21 (d, J=5.5 Hz, 3H), 3.87(s, 3H), 3.09 (s, 3H), 3.06 (s, 2H), 2.21 (s, 1H), 2.10 (s, 4H), 1.96(d, J=20.0 Hz, 1H), 1.70 (dd, J=10.0, 4.6 Hz, 1H), 1.62-1.44 (m, 1H).

Compound 678.(S)-7-(2-methoxyethyl)-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.62 (s, 1H), 7.51 (s, 1H), 6.48 (s,1H), 5.57-5.30 (m, 3H), 4.83 (s, 3H), 4.38 (s, 2H), 4.16 (dd, J=6.1, 4.0Hz, 1H), 3.84 (s, 3H), 3.14-2.99 (m, 6H), 2.21-1.89 (m, 5H).

Compound 704.7-(methoxymethyl)-4,7,8-trimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6-d6) δ 9.88 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H),6.59 (s, 2H), 5.45 (s, 2H), 4.23 (d, J=6.0 Hz, 2H), 3.89 (d, J=8.3 Hz,3H), 3.66 (d, J=10.0 Hz, 1H), 3.55 (d, J=10.0 Hz, 1H), 3.20 (s, 3H),2.98 (s, 3H), 2.11 (s, 3H), 1.40-1.29 (m, 3H).

Compound 709.7-(methoxymethyl)-4,7,8-trimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H),6.58 (s, 1H), 6.48 (s, 1H), 5.44 (s, 2H), 4.21 (d, J=6.1 Hz, 2H), 3.87(s, 3H), 3.65 (d, J=10.0 Hz, 1H), 3.54 (d, J=10.1 Hz, 1H), 3.19 (s, 3H),2.96 (s, 3H), 2.10 (s, 3H), 1.32 (s, 3H).

Example 2S

Table 17 shows certain compounds prepared by the Method A procedure byreaction of Intermediate A-# and B-39 (See procedure for compound 46).¹H NMR data are also provided for certain compounds.

TABLE 17 Comp. No. R₃ = [α]_(D) M + 1 728

+112.1° c = 0.5 MeOH 436.13 727 -iPr +107.9° 420.16 c = 0.5 MeOH

Compound 728.(S)-2-(((1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-((R)-1-methoxyethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.59 (s, 1H), 7.47 (s, 1H), 4.39 (s,2H), 4.19 (d, J=5.2 Hz, 2H), 4.04-3.87 (m, 1H), 3.69-3.45 (m, 1H), 2.60(d, J=7.2 Hz, 3H), 2.35 (d, J=7.1 Hz, 2H), 2.24-2.06 (m, 3H), 1.19 (d,J=6.4 Hz, 3H).

Compound 727.(S)-2-(((1-((3,3-difluorocyclobutyl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.58 (s, 1H), 7.46 (s, 1H), 4.38 (s,2H), 4.19 (d, J=3.8 Hz, 2H), 3.96-3.85 (m, 1H), 3.14 (s, 3H), 2.72-2.47(m, 3H), 2.46-2.08 (m, 6H), 1.03 (d, J=7.0 Hz, 3H), 0.87 (d, J=6.9 Hz,3H).

Example 2T

Table 18 provides certain compounds that were prepared by the Method Aprocedure by reaction of Intermediates A-# and B-# (See procedure forCompound 46). ¹H NMR data are also provided for certain compounds.

TABLE 18 Comp. No. L-Ring A R₃ = R₄ = Int A Int B [α]_(D) M + 1 417

—Et —H A-8  B-166 +36.6° c = 0.5 CHCl₃ 459.27 421

-cPr —H A-6  B-53  +29.2° c = 0.5 CHCl₃ 423.29 422

-iPr —H A-9  B-166 +43.4° c = 0.5 CHCl₃ 473.41 423

-iPr —H A-9  B-54  +36.7° c = 0.5 CHCl₃ 439.55 425

-iPr —H A-9  B-169 +49° c = 0.55 CHCl₃ 439.19 427

—Et —H A-8  B-52  447.34 429

-iPr —H A-9  B-64  +47.4° c = 0.5 CHCl₃ 437.39 433

—Et —H A-8  B-83  68 c = 0.5 MeOH 491.46 435

-cPr —H A-6  B-83  36.88 c = 1.0 MeOH 503.57 437

-tBu —H A-55 B-53  +54.6° c = 0.5 CHCl₃ 439.24 439

CH₂CH₂OH —H A-25 B-52  463.5 440

—Et —H A-8  B-171 59.3 c = 0.5 CHCl₃ 433.38 441

-cPr —H A-6  B-171 47.1 c = 0.5 CHCl₃ 445.4 442

-iPr —H A-9  B-171 62.4 c = 0.5 CHCl₃ 447.34 444

—CH₃ —H A-2  B-172 41.35 c = 0.5 MeOH 461.47 447

-iPr —H A-9 B-71  68.3 c = 1 MeOH 475.48 448

-iPr —H A-9  CA 56.8 c = 0.5 CHCl₃ 450.53 449

-iPr —H A-9  B-23  78.3 c = 0.5 CHCl₃ 460.44 450

-iPr —H A-9 B-20  74.3 c = 0.5 CHCl₃ 472.42 454

-iPr —H A-9  B-174 88.16 c = 0.5 MeOH 425.45 455

-cPr —H A-6  B-71  41.3 c = 41.3 MeOH 473.45 456

-cPr —H A-6  B-23  34.5 c = 0.5 CHCl₃ 458.46 457

-cPr —H A-6  B-20  28.2 c = 0.5 CHCl₃ 470.48 466

-cPr —H A-6  CA 47.9 c = 0.5 CHCl₃ 448.51 467

-iPr —H A-9  B-175 489.49 468

—CH₃ —H A-2  B-176 83.14 c = 0.35 MeOH 433.38 469

-iPr —H A-9  B-177 72.7 c = 0.5 CHCl₃ 463.5 470

-iPr —H A-9  B-178 73.4 c = 0.5 CHCl₃ 474.44 479

-iPr —H A-9  B-2  74.00 c = 0.5 MeOH 424.46 480

-iPr —H A-9  B-179 447.43 492

—CH₃ —H A-2  B-183 30.7 c = 1 MeOH 475.34 500

-iPr —H A-9  B-182 68.8 c = 0.5 CHCl₃ 457.33 501

-cPr —H A-6  B-182 47 c = 0.5 CHCl₃ 455.36 510

-iPr —H A-9  B-184 491.07 511

-iPr —H A-9  B-185 67.9 c = 0.5 CHCl₃ 471.33 516

—Et —H A-8  B-93  54.8 c = 0.5 CHCl₃ 450.35 518

-iPr —H A-9  B-93  72.6 c = 0.5 CHCl₃ 464.31 565

—H A-59 B-184 62.6 c = 0.5 CHCl₃ 507.35 658

—H A-59 B-2  440.25 659

—H A-59 B-23  476.25 668

—H A-66 B-23  75.6 c = 1 MeOH 502.23 729

—H A-61 B-23  +50.2° c = 0.5 MeOH 476.3 741

—H A-63 B-23  +51.5° c = 0.5 MeOH 504.47 705

—CH₂OCH₃ —CH₃ A-69 B-23  +50.3° c = 0.5 MeOH 476.26 708

—CH₃ CH₂OCH₃ A-70 B-23  −48.1° c = 0.5 MeOH 476.26 747

—H A-72 B-23  517.24 746

—H A-72 B-20  51.52 c = 0.5 MeOH

Compound 417.(7S)-2-(((1-((6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.08 (d, J=2.5 Hz, 1H), 7.59 (dd,J=8.5, 2.5 Hz, 1H), 7.52 (s, 1H), 7.36 (s, 1H), 7.61-7.19 (t, 1H), 6.87(d, J=8.5 Hz, 1H), 5.23 (s, 2H), 4.82 (d, J=5.8 Hz, 1H), 4.40 (d, J=5.7Hz, 2H), 4.06 (dd, J=6.4, 3.7 Hz, 1H), 3.04 (s, 3H), 2.17 (s, 3H), 1.96(dtd, J=15.2, 7.6, 3.9 Hz, 1H), 1.83 (dt, J=14.3, 7.1 Hz, 1H), 0.88 (t,J=7.6 Hz, 3H).

Compound 421.(7S)-7-cyclopropyl-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.11 (dt, J=2.6, 0.9 Hz,1H), 7.65 (ddd, J=8.3, 7.6, 2.6 Hz, 1H), 7.53 (d, J=0.7 Hz, 1H),7.46-7.35 (m, 1H), 6.98-6.84 (m, 1H), 5.49 (s, 1H), 5.26 (s, 2H), 4.44(dd, J=5.6, 1.7 Hz, 2H), 3.29 (d, J=9.1 Hz, 1H), 3.14 (s, 3H), 2.26 (s,3H), 1.38-1.13 (m, 1H), 1.07-0.90 (m, 1H), 0.76-0.63 (m, 1H), 0.63-0.38(in, 2H)

Compound 422.(7S)-2-(((1-((6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.10 (d, J=2.4 Hz, 1H),7.61 (dd, J=8.5, 2.5 Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.25 (d,J=21.3 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.25 (s, 2H), 4.91 (d, J=5.8 Hz,1H), 4.42 (d, J=5.7 Hz, 2H), 3.89 (d, J=4.3 Hz, 1H), 3.11 (s, 3H),2.33-2.23 (m, 1H), 2.21 (s, 3H), 1.07 (dd, J=6.9, 1.8 Hz, 3H), 0.97-0.89(m, 4H).

Compound 423.(7S)-2-(((1-((6-fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.78 (s, 1H), 7.52 (s,1H), 6.70 (m, 1H), 5.27 (s, 2H), 4.81 (t, J=5.7 Hz, 1H), 4.41 (d, J=5.7Hz, 2H), 3.89 (d, J=4.3 Hz, 1H), 3.11 (s, 3H), 2.38-2.27 (m, 3H),2.26-2.19 (m, 1H), 2.19 (s, 3H), 1.08 (d, J=6.9 Hz, 3H), 0.99-0.81 (m,3H).

Compound 425.(7S)-2-(((1-((5-fluoro-6-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.23 (d, J=1.5 Hz, 1H), 7.54 (s, 1H),7.42 (s, 1H), 7.17 (dd, J=9.7, 1.9 Hz, 1H), 5.95-5.52 (m, 1H), 5.27 (s,2H), 4.45 (d, J=5.7 Hz, 2H), 3.92 (d, J=4.3 Hz, 1H), 3.15 (s, 3H), 2.52(d, J=2.9 Hz, 3H), 2.38-2.26 (m, 1H), 2.25 (s, 3H), 1.09 (d, J=7.0 Hz,3H), 0.93 (d, J=6.9 Hz, 3H).

Compound 427.(7S)-7-ethyl-8-methyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.65-8.54 (m, 1H), 7.74-7.61 (m, 2H),7.59 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 6.54 (s, 1H), 5.38 (s, 2H),4.47 (d, J=5.7 Hz, 2H), 4.13 (dd, J=6.0, 3.4 Hz, 1H), 3.09 (s, 3H),2.13-1.78 (m, 2H), 0.89 (d, J=7.5 Hz, 3H).

Compound 429.(7S)-7-isopropyl-2-(((1-((6-methoxypyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.02-7.95 (m, 1H), 7.42 (d, J=0.7 Hz,1H), 7.38 (dd, J=8.6, 2.5 Hz, 1H), 7.31-7.23 (m, 1H), 6.63 (dd, J=8.5,0.7 Hz, 1H), 5.46 (s, 1H), 5.10 (s, 2H), 4.33 (d, J=5.5 Hz, 2H), 3.85(s, 3H), 3.82-3.75 (m, 1H), 3.03 (s, 3H), 2.16 (s, 4H), 0.99 (d, J=7.0Hz, 3H), 0.84 (d, J=6.9 Hz, 3H).

Compound 433.(7S)-7-ethyl-4,8-dimethyl-2-(((1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.12 (d, J=2.3 Hz, 1H),7.73-7.63 (m, 2H), 7.37 (s, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.60 (t, J=5.8Hz, 1H), 5.24 (s, 2H), 4.96 (q, J=9.1 Hz, 2H), 4.22 (d, J=6.0 Hz, 2H),4.01 (dd, J=6.5, 3.7 Hz, 1H), 2.97 (s, 3H), 2.12 (s, 3H), 1.89-1.59 (m,2H), 0.74 (t, J=7.4 Hz, 3H).

Compound 435.(7S)-7-cyclopropyl-4,8-dimethyl-2-(((1-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.12 (d, J=2.4 Hz, 1H),7.73-7.62 (m, 2H), 7.38 (d, J=0.8 Hz, 1H), 6.94 (dd, J=8.5, 0.7 Hz, 1H),6.56 (t, J=6.1 Hz, 1H), 5.24 (s, 2H), 4.96 (q, J=9.1 Hz, 2H), 4.22 (dd,J=6.1, 3.32 (d, J=7.0 Hz, 1H), 2.6 Hz, 2H), 3.02 (s, 3H), 2.14 (s, 3H),0.83 (ddt, J=12.9, 8.0, 3.9 Hz, 1H), 0.63-0.25 (m, 4H).

Compound 437.(7S)-7-(tert-butyl)-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.14 (d, J=2.5 Hz, 1H), 7.78 (s, 1H),7.73-7.59 (m, 1H), 7.55 (s, 1H), 7.40 (s, 1H), 6.92 (dd, J=8.4, 3.0 Hz,1H), 5.27 (s, 2H), 4.90 (s, 1H), 4.44 (d, J=5.8 Hz, 2H), 3.71 (s, 1H),3.21 (s, 3H), 2.20 (s, 3H), 1.01 (s, 9H).

Compound 439.(S)-7-(2-hydroxyethyl)-4-methyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.65 (d, J=1.9 Hz, 1H),7.93-7.83 (m, 2H), 7.80 (s, 1H), 7.46 (s, 1H), 6.94 (brs, 1H), 5.45 (s,2H), 4.61 (t, J=5.1 Hz, 1H), 4.24 (d, J=5.9 Hz, 2H), 4.11-3.98 (m, 1H),3.53 (m, 2H), 2.14 (s, 3H), 1.93-1.85 (m, 2H).

Compound 440.(7S)-7-(2-hydroxyethyl)-4-methyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.35 (d, J=2.3 Hz, 1H), 7.73 (s, 1H),7.52 (s, 1H), 7.41 (dd, J=8.1, 2.4 Hz, 1H), 7.35 (s, 1H), 7.11 (d, J=8.0Hz, 1H), 5.22 (s, 2H), 4.86 (s, 1H), 4.41 (d, J=5.7 Hz, 2H), 4.08 (dd,J=6.4, 3.7 Hz, 1H), 3.06 (s, 3H), 2.19 (s, 3H), 2.10-1.94 (m, 2H),1.91-1.80 (m, 1H), 1.01 (d, J=5.4 Hz, 3H), 0.90 (td, J=7.3, 2.2 Hz, 4H).

Compound 441.(7S)-7-cyclopropyl-2-(((1-((6-cyclopropylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.39-8.27 (m, 1H), 7.81 (s, 1H), 7.53(d, J=0.8 Hz, 1H), 7.41 (dd, J=8.1, 2.4 Hz, 1H), 7.11 (dd, J=8.1, 0.8Hz, 1H), 5.22 (s, 2H), 4.85 (d, J=6.0 Hz, 1H), 4.49-4.34 (m, 2H), 3.30(d, J=9.0 Hz, 1H), 3.13 (s, 3H), 2.23 (s, 3H), 2.10-1.96 (m, 1H),1.07-0.94 (m, 5H), 0.78-0.44 (m, 3H).

Compound 442.(7S)-2-(((1-((6-cyclopropylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.34 (d, J=2.3 Hz, 1H), 7.54-7.49 (m,1H), 7.40 (dd, J=8.1, 2.4 Hz, 1H), 7.35 (s, 2H), 7.11 (dd, J=8.1, 0.9Hz, 1H), 5.22 (s, 2H), 5.04 (s, 1H), 4.41 (d, J=5.7 Hz, 2H), 3.89 (d,J=4.3 Hz, 1H), 3.11 (s, 3H), 2.21 (m, 4H), 2.12-1.94 (m, 1H), 1.07 (d,J=7.0 Hz, 3H), 1.05-0.97 (m, 4H), 0.92 (d, J=7.0 Hz, 3H).

Compound 444.(7S)-4,7,8-trimethyl-2-(((1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.46 (s, 1H), 7.76 (brs, 3H),7.57 (s, 1H), 7.41 (s, 1H), 4.38 (t, J=6.9 Hz, 2H), 4.30 (d, J=4.9 Hz,2H), 4.23 (q, J=6.8 Hz, 1H), 3.21 (t, J=6.9 Hz, 2H), 3.09 (s, 3H), 2.22(s, 3H), 1.35 (d, J=6.9 Hz, 3H).

Compound 447.(S)-7-isopropyl-4,8-dimethyl-2-(((1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.65 (s, 1H), 7.88 (s, 1H), 7.65 (s,1H), 7.51 (s, 1H), 7.39 (s, 1H), 5.51 (s, 2H), 4.56 (s, 2H), 4.15 (s,1H), 3.28 (s, 3H), 2.29 (s, 3H), 1.11 (d, J=5.8 Hz, 3H), 0.88 (d, J=5.7Hz, 3H).

Compound 448.(S)-2-(((1-((2-(dimethylamino)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.11 (dd, J=5.2, 0.8 Hz, 2H), 7.55 (d,J=0.8 Hz, 1H), 7.39 (d, J=0.8 Hz, 1H), 6.31 (dd, J=5.1, 1.4 Hz, 1H),6.26 (dd, J=1.5, 0.8 Hz, 1H), 5.17 (s, 2H), 4.81 (t, J=5.7 Hz, 1H), 4.43(d, J=5.7 Hz, 2H), 3.89 (d, J=4.4 Hz, 1H), 3.11 (s, 3H), 3.06 (s, 7H),2.63 (s, 5H), 2.30-2.21 (m, 1H), 2.20 (s, 3H), 1.07 (d, J=7.0 Hz, 3H),0.97-0.91 (m, 3H).

Compound 449.(S)-7-isopropyl-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.85 (s, 1H), 7.65 (s, 1H), 7.03 (dd,J=8.4, 6.4 Hz, 2H), 5.36 (s, 2H), 4.60 (s, 2H), 4.21 (d, J=3.5 Hz, 1H),3.34 (s, 3H), 2.36 (s, 3H), 1.17 (d, J=6.7 Hz, 3H), 0.95 (d, J=6.7 Hz,3H).

Compound 450.(S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.83 (s, 1H), 7.63 (s, 1H), 6.89 (d,J=8.7 Hz, 2H), 5.31 (s, 2H), 4.59 (s, 2H), 4.21 (d, J=3.3 Hz, 1H), 3.98(s, 3H), 3.33 (s, 3H), 2.35 (s, 3H), 1.17 (d, J=6.5 Hz, 3H), 0.94 (d,J=6.4 Hz, 3H).

Compound 454.(S)-2-(((1-((5-fluoropyridin-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.51 (d, J=2.9 Hz, 1H), 7.73(s, 1H), 7.71-7.60 (m, 1H), 7.42 (s, 1H), 7.14 (dd, J=8.7, 4.5 Hz, 1H),5.37 (s, 2H), 4.30 (d, J=5.9 Hz, 2H), 3.97 (d, J=4.2 Hz, 1H), 2.16 (s,3H), 0.96 (d, J=6.9 Hz, 3H), 0.77 (d, J=6.8 Hz, 3H).

Compound 455.(S)-7-cyclopropyl-4,8-dimethyl-2-(((1-((2-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.65 (d, J=5.1 Hz, 1H), 7.84 (d, J=0.8Hz, 1H), 7.64 (d, J=0.8 Hz, 1H), 7.50 (s, 1H), 7.39 (d, J=5.1 Hz, 1H),5.50 (s, 2H), 4.56 (s, 2H), 3.63 (d, J=9.0 Hz, 1H), 3.33 (s, 3H), 2.31(s, 3H), 1.24-1.00 (m, 1H), 0.83-0.51 (m, 3H).

Compound 456.(S)-7-cyclopropyl-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.79 (d, J=0.8 Hz, 1H), 7.59 (d, J=0.8Hz, 1H), 7.07-6.87 (m, 2H), 5.30 (d, J=1.0 Hz, 2H), 4.54 (s, 2H), 3.63(d, J=9.0 Hz, 1H), 3.34 (d, J=3.9 Hz, 3H), 2.31 (s, 3H), 1.22-1.02 (m,1H), 0.83-0.53 (m, 3H).

Compound 457.(S)-7-cyclopropyl-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.76 (s, 1H), 7.58 (d, J=0.8 Hz, 1H),6.93-6.75 (m, 2H), 5.25 (s, 2H), 4.53 (s, 2H), 3.92 (t, J=1.0 Hz, 3H),3.63 (d, J=9.0 Hz, 1H), 2.30 (s, 3H), 1.19-1.01 (m, OH), 0.84-0.48 (m,3H).

Compound 466.(S)-7-cyclopropyl-2-(((1-((2-(dimethylamino)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.90 (s, 1H), 7.83 (d, J=6.3 Hz, 1H),7.65 (s, 1H), 6.98 (s, 1H), 6.62 (d, J=6.4 Hz, 1H), 5.45 (s, 2H), 4.57(s, 2H), 3.64 (d, J=8.2 Hz, 1H), 3.36 (s, 3H), 2.32 (s, 3H), 1.12 (s,1H), 0.81-0.54 (m, 5H).

Compound 467.(S)-7-isopropyl-4,8-dimethyl-2-(((1-(4-(trifluoromethoxy)benzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.72 (s, 1H), 7.42 (s, 1H),7.32 (s, 4H), 5.31 (s, 2H), 4.30 (d, J=5.7 Hz, 2H), 3.99 (s, 1H), 3.09(s, 3H), 2.16 (s, 4H), 0.97 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9 Hz, 3H).

Compound 468.(S)-4,7,8-trimethyl-2-(((1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 9.25 (d, J=2.5 Hz, 1H), 8.60(s, 1H), 8.44 (dd, J=8.6, 2.6 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.84 (s,1H), 6.77 (t, J=6.0 Hz, 1H), 4.34 (dd, J=5.9, 2.3 Hz, 2H), 4.01 (q,J=6.7 Hz, 1H), 2.96 (s, 3H), 2.15 (s, 3H), 1.20 (d, J=6.8 Hz, 3H).

Compound 469.(S)-2-(((1-((6-(tert-butyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.50-8.42 (m, 1H), 7.61 (d, J=9.2 Hz,1H), 7.54 (d, J=0.7 Hz, 1H), 7.48 (dd, J=8.2, 2.4 Hz, 1H), 7.43-7.37 (m,1H), 7.33 (dd, J=8.3, 0.9 Hz, 1H), 5.26 (s, 2H), 4.81 (s, 1H), 4.42 (d,J=5.7 Hz, 2H), 3.90 (d, J=4.3 Hz, 1H), 3.12 (s, 3H), 2.24 (td, J=7.0,4.5 Hz, 1H), 2.19 (s, 3H), 1.37 (s, 9H), 1.08 (d, J=7.0 Hz, 3H), 0.92(d, J=7.0 Hz, 3H).

Compound 470.(S)-2-(5-((4-(((7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)-2-methylpropanenitrile

¹H NMR (300 MHz, Chloroform-d) δ 8.73 (s, 1H), 8.48 (d, J=1.7 Hz, 1H),7.71-7.52 (m, 3H), 7.42 (s, 1H), 5.29 (s, 2H), 4.99 (s, 1H), 4.43 (d,J=5.7 Hz, 2H), 3.89 (d, J=4.3 Hz, 1H), 3.12 (s, 4H), 2.22 (s, 5H), 1.75(s, 6H), 1.07 (d, J=7.0 Hz, 3H), 0.92 (d, J=7.0 Hz, 3H).

Compound 479.(S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.68-7.60 (m, 1H), 7.37 (d,J=0.8 Hz, 1H), 7.31-7.22 (m, 2H), 7.14 (t, J=8.9 Hz, 1H), 6.48 (t, J=6.1Hz, 1H), 5.23 (s, 2H), 4.21 (d, J=6.1 Hz, 2H), 3.91-3.77 (m, 1H), 3.01(s, 3H), 2.10 (s, 3H), 0.93 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H).

Compound 480.(S)-7-isopropyl-4,8-dimethyl-2-(((1-((6-(prop-1-en-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.39 (d, J=2.3 Hz, 1H), 7.91 (s, 1H),7.44 (s, 1H), 7.40 (dd, J=7.1, 1.6 Hz, 1H), 7.30 (s, 1H), 5.82-5.72 (m,1H), 5.24 (p, J=1.6 Hz, 1H), 5.19 (s, 2H), 4.34 (d, J=5.7 Hz, 2H), 3.81(d, J=4.3 Hz, 1H), 3.03 (s, 2H), 2.12 (d, J=1.5 Hz, 4H), 0.99 (d, J=7.0Hz, 2H), 0.87-0.81 (m, 3H)

Compound 492.(S)-4,7,8-trimethyl-2-(((1-(3-(6-(trifluoromethyl)pyridin-3-yl)propyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 7.90(dd, J=8.1, 2.1 Hz, 1H), 7.80 (dd, J=8.1, 0.8 Hz, 1H), 7.64 (s, 1H),7.38 (s, 1H), 7.13 (s, 1H), 4.28 (dd, J=5.8, 1.9 Hz, 2H), 4.16-4.07 (m,3H), 3.03 (s, 3H), 2.65 (t, J=7.7 Hz, 2H), 2.18 (s, 3H), 2.13-1.95 (m,2H), 1.26 (d, J=6.9 Hz, 3H).

Compound 500.(S)-2-(((1-((6-(difluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 9.27 (s, 1H), 8.56-8.47 (m, 1H),7.72-7.57 (m, 2H), 7.56-7.49 (m, 1H), 7.44 (s, 1H), 6.61 (t, J=55.4 Hz,1H), 5.81 (s, 1H), 5.33 (s, 2H), 4.43 (d, J=5.7 Hz, 2H), 3.88 (d, J=4.3Hz, 1H), 3.11 (s, 3H), 2.25 (s, 4H), 1.06 (d, J=7.0 Hz, 3H), 0.91 (d,J=6.9 Hz, 3H).

Compound 501.(S)-7-cyclopropyl-2-(((1-((6-(difluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 9.24 (s, 1H), 8.26 (s, 1H), 7.46-7.32(m, 2H), 7.30 (s, 1H), 7.17 (s, 1H), 6.37 (t, J=55.4 Hz, 1H), 5.08 (s,2H), 4.93 (s, 1H), 4.19 (dd, J=5.7, 1.7 Hz, 2H), 3.03 (d, J=8.9 Hz, 1H),2.87 (s, 3H), 2.02 (s, 3H), 0.74 (dtd, J=13.1, 8.4, 5.1 Hz, 1H),0.52-0.13 (m, 4H).

Compound 510.(S)-7-isopropyl-4,8-dimethyl-2-(((1-((6-(trifluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.17 (d, J=2.4 Hz, 1H), 7.76 (dd, J=8.4,2.5 Hz, 1H), 7.68 (s, 1H), 7.51 (s, 1H), 7.10 (d, J=8.5 Hz, 1H), 5.48(d, J=0.6 Hz, 1H), 5.35 (s, 2H), 4.39 (s, 2H), 3.89 (d, J=4.5 Hz, 1H),3.11 (s, 3H), 2.15 (s, 4H), 1.01 (d, J=6.9 Hz, 3H), 0.84 (d, J=6.9 Hz,3H).

Compound 511.(S)-2-(((1-((6-(1,1-difluoroethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.52 (s, 1H), 8.10 (s, 1H), 7.56 (s,1H), 7.41 (s, 1H), 5.33 (s, 2H), 4.85 (t, J=5.8 Hz, 1H), 4.44 (d, J=5.8Hz, 2H), 3.89 (d, J=4.4 Hz, 1H), 3.11 (s, 3H), 2.33-2.23 (m, 1H), 2.20(s, 3H), 2.02 (t, J=18.6 Hz, 3H), 1.08 (d, J=6.9 Hz, 3H), 0.94 (s, 3H).[

Compound 516.(S)-7-ethyl-4,8-dimethyl-2-(((1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 7.42 (d, J=0.7 Hz, 1H), 7.35 (d, J=0.8Hz, 1H), 6.65 (dq, J=3.6, 1.2 Hz, 1H), 6.27 (dq, J=2.5, 0.8 Hz, 1H),5.19 (s, 2H), 5.04-4.90 (m, 1H), 4.33 (d, J=5.8 Hz, 2H), 3.96 (dd,J=6.4, 3.8 Hz, 1H), 2.97 (s, 3H), 2.15 (s, 3H), 1.95-1.67 (m, 2H), 0.82(t, J=7.5 Hz, 3H).

Compound 518.(S)-7-isopropyl-4,8-dimethyl-2-(((1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 9.42 (s, 1H), 7.51 (d, J=3.3 Hz, 1H),7.43 (d, J=2.6 Hz, 1H), 6.73 (td, J=3.2, 1.5 Hz, 1H), 6.35 (t, J=3.6 Hz,1H), 5.27 (d, J=3.7 Hz, 2H), 5.05 (s, 1H), 4.42 (t, J=4.3 Hz, 2H), 3.86(t, J=3.7 Hz, 1H), 3.10 (d, J=3.2 Hz, 3H), 2.23 (d, J=0.9 Hz, 4H), 1.06(dd, J=6.6, 2.8 Hz, 3H), 1.01-0.77 (m, 3H).

Compound 565.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.21 (dd, J=2.5, 0.8 Hz, 1H), 7.82 (s,1H), 7.65 (dd, J=8.4, 2.5 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.41 (d,J=0.8 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 4.86 (t, J=5.7 Hz,1H), 4.44 (d, J=5.8 Hz, 2H), 3.95 (d, J=6.0 Hz, 1H), 3.58 (p, J=6.2 Hz,1H), 3.31 (s, 3H), 3.19 (s, 3H), 2.22 (s, 3H), 1.40-1.27 (m, 7H), 1.24(d, J=6.4 Hz, 3H).

Compound 658.(S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-((R)-1-methoxyethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J=0.8 Hz, 1H), 7.45 (d, J=0.7 Hz,1H), 7.30-7.25 (m, 2H), 7.20-7.12 (m, 2H), 5.27 (s, 2H), 4.47-4.33 (m,2H), 4.30 (d, J=4.0 Hz, 1H), 3.71 (qd, J=6.5, 4.0 Hz, 1H), 3.24 (s, 3H),3.19 (s, 3H), 3.10 (qd, J=7.3, 4.8 Hz, 1H), 2.24 (s, 3H), 1.21-1.15 (m,4H).

Compound 659.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d4) δ 7.77 (s, 1H), 7.05-6.89 (m, 2H), 5.32(d, J=14.7 Hz, 2H), 4.53 (s, 2H), 4.23 (d, J=3.9 Hz, 1H), 3.89 (d,J=19.8 Hz, 1H), 3.78 (d, J=8.2 Hz, 2H), 2.38 (2, 5H), 1.28 (d, J=6.5 Hz,6H).

Compound 668.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.69 (s, 1H), 7.41 (s, 1H),7.12 (dd, J=8.7, 6.8 Hz, 2H), 6.50 (s, 1H), 5.26 (s, 2H), 4.29-4.12 (m,3H), 3.09 (s, 3H), 3.06 (s, 3H), 2.28-2.17 (m, 1H), 2.12 (d, J=12.7 Hz,5H), 1.97 (dd, J=19.0, 9.2 Hz, 1H), 1.68 (ddd, J=20.4, 9.4, 5.5 Hz, 1H),1.56 (dt, J=9.1, 8.0 Hz, 1H).

Compound 729.(S)-7-(2-hydroxypropan-2-yl)-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.71 (s, 1H), 7.43 (s, 1H),7.13 (dd, J=8.7, 6.8 Hz, 2H), 6.59 (s, 1H), 5.26 (s, 2H), 4.70 (s, 1H),4.25 (d, J=4.1 Hz, 2H), 3.81 (s, 1H), 3.20-3.07 (m, 4H), 2.14 (d, J=32.3Hz, 3H), 1.18 (s, 3H), 0.92 (s, 3H).

Compound 741.(S)-7-(tert-butoxymethyl)-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.03 (d, J=106.2 Hz, 1H), 7.46 (s, 1H),7.32 (s, 1H), 6.86-6.54 (m, 2H), 5.42 (s, 1H), 5.10 (s, 2H), 4.37 (d,J=5.7 Hz, 2H), 4.01 (t, J=3.0 Hz, 1H), 3.63 (t, J=3.4 Hz, 2H), 3.14-2.94(m, 3H), 2.22-2.03 (m, 3H), 1.07-0.87 (m, 9H).

Compound 746.(S)-7-((S)-1-(tert-butoxy)ethyl)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J=14.9 Hz, 2H), 6.80-6.69 (m,2H), 5.18 (s, 2H), 4.49 (dd, J=5.4, 2.8 Hz, 2H), 4.12 (pd, J=7.4, 6.4,4.2 Hz, 1H), 4.02-3.95 (m, 4H), 3.29 (s, 3H), 2.37 (s, 3H), 1.24 (d,J=6.4 Hz, 3H), 1.06 (s, 9H).

Compound 747.(S)-7-((S)-1-(tert-butoxy)ethyl)-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, CDCl₃) δ 7.54 (d, J=0.7 Hz, 1H), 7.50 (d, J=0.8 Hz,1H), 6.82-6.70 (m, 2H), 5.16 (d, J=0.9 Hz, 2H), 4.42 (t, J=4.0 Hz, 2H),4.05 (tt, J=6.9, 3.4 Hz, 1H), 3.96 (d, J=2.1 Hz, 1H), 3.24 (s, 3H), 2.26(s, 3H), 1.18 (d, J=6.4 Hz, 3H), 0.96 (s, 9H).

Example 2U

Table 19 provides certain compounds that were prepared by the Method Bprocedure by reaction of Intermediates A-# and B-# (See procedure forCompound 1). ¹H NMR data for certain compounds are also provided.

TABLE 19 Comp. No. L-Ring A R₃ = Int A Int B [α]_(D) M + 1 414

-iPr A-9  B-67  +61.2 c = 1 MeOH 441.26 415

-iPr A-9  B-78  425.45 418

—CH₃ A-2  B-167 481.28 424

-iPr A-9  B-168 459.31 426

—Et A-8  B-168 445.36 431

-iPr A-9  B-170 432.43 432

—Et A-8  B-67  +45.2 c = 0.5 MeOH 427.25 434

-cPr A-6  B-67  +33 c = 1.0 MeOH 439.32 438

-tBu A-55 B-67  +79.2 c = 1.0 CHCl₃ 455.22 443 (R₁ = Me)

CH₂CH₂OH A-56 B-52  +46.3 c = 0.5 MeOH 491.28 445 (R₁ = Me)

CH₂CH₂OH A-56 B-67  +46.9 c = 0.55 MeOH 457.05 446

-iPr A-9  CA +78.7 C = 1.0 CHCl₃ 441.39 608

-cPr A-6  CA +44.7 c = 0.5 CHCl₃ 439.46 499

A-59 B-67  +68.9 c = 0.6 MeOH 457.33 491

iPr A-9  B-181 +48.5 c = 1, MeOH 447.34 517

-iPr A-9  B-186 +77.8 c = 0.5 CHCl₃ 439.32 513

—Et A-8  B-186 +72.5 c = 0.5 CHCl₃ 477.25 550

A-60 B-67  +91.4 c = 0.5 CHCl₃ 455.26

Compound 414.(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 12.73 (s, 1H), 10.52 (s, 1H), 8.31 (d, J=2.1Hz, 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.70 (dd, J=8.2, 2.5 Hz, 1H), 7.50(d, J=8.0 Hz, 2H), 5.35 (s, 2H), 4.41 (d, J=5.7 Hz, 2H), 4.16 (d, J=3.7Hz, 1H), 3.18 (s, 3H), 2.35-2.12 (m, 4H), 1.01 (d, J=6.9 Hz, 3H), 0.77(d, J=6.9 Hz, 3H).

Compound 415.(7S)-2-(((1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.96 (t, J=2.3 Hz, 1H), 8.68 (d, J=1.5Hz, 1H), 8.28 (dd, J=8.7, 2.1 Hz, 1H), 8.00 (s, 1H), 7.69 (s, 1H), 5.66(s, 2H), 4.59 (d, J=2.1 Hz, 2H), 4.19 (d, J=3.9 Hz, 1H), 2.46-2.34 (m,OH), 2.33 (s, 3H), 1.14 (d, J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).

Compound 418.(7S)-2-(((1-((2-chloro-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.78(s, 1H), 7.54-7.43 (m, 2H), 6.65 (t, J=6.1 Hz, 1H), 5.49 (s, 2H), 4.24(d, J=6.2 Hz, 2H), 4.00 (q, J=6.7 Hz, 1H), 2.94 (s, 3H), 2.13 (s, 3H),1.18 (d, J=6.8 Hz, 3H).

Compound 424.(7S)-2-(((1-((6-chloro-5-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.13 (d, J=2.0 Hz, 1H), 7.67 (s, 1H),7.57 (s, 1H), 7.41 (s, 1H), 7.31 (dd, J=8.4, 2.1 Hz, 1H), 5.29 (s, 2H),4.82 (t, J=5.8 Hz, 1H), 4.44 (d, J=5.8 Hz, 2H), 3.90 (d, J=4.3 Hz, 1H),3.12 (s, 3H), 2.24 (td, J=6.9, 4.4 Hz, 1H), 2.19 (s, 3H), 1.64 (s, 6H),1.08 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H).

Compound 426.(7S)-2-(((1-((6-chloro-5-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.16-8.05 (m, 1H), 7.54 (s, 1H), 7.39(d, J=0.8 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 5.27 (s, 2H), 4.84 (d, J=5.9Hz, 1H), 4.42 (d, J=5.8 Hz, 2H), 4.06 (dd, J=6.4, 3.7 Hz, 1H), 3.05 (s,3H), 2.18 (s, 3H), 1.97 (dqd, J=15.3, 7.8, 4.0 Hz, 1H), 1.83 (dt,J=14.3, 7.1 Hz, 1H), 0.93-0.86 (m, 3H).

Compound 431.(7S)-5-((4-(((7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)picolinonitrile

¹H NMR (300 MHz, Methanol-d₄) δ 8.51 (d, J=1.7 Hz, 1H), 7.96-7.75 (m,3H), 7.62 (s, 1H), 5.49 (s, 2H), 4.54 (s, 2H), 4.15 (d, J=3.8 Hz, 1H),3.27 (s, 3H), 2.43-2.29 (m, 1H), 2.29 (s, 3H), 1.11 (d, J=7.0 Hz, 3H),0.88 (d, J=6.9 Hz, 3H).

Compound 432.(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.30 (d, J=2.5 Hz, 1H),7.75-7.62 (m, 2H), 7.47 (dd, J=8.2, 0.8 Hz, 1H), 7.39 (d, J=0.8 Hz, 1H),6.50 (t, J=6.1 Hz, 1H), 5.31 (s, 2H), 4.21 (d, J=6.0 Hz, 2H), 3.99 (dd,J=6.6, 3.8 Hz, 1H), 2.96 (s, 3H), 2.11 (s, 3H), 1.89-1.53 (m, 2H), 0.74(t, J=7.4 Hz, 3H)

Compound 434.(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-cyclopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 7.78(s, 1H), 7.68 (dd, J=8.3, 2.5 Hz, 1H), 7.55-7.42 (m, 3H), 5.34 (s, 2H),4.33 (dd, J=5.7, 2.8 Hz, 2H), 3.52 (d, J=8.9 Hz, 1H), 3.13 (s, 3H), 2.20(s, 3H), 1.09-0.86 (m, 1H), 0.68-0.32 (m, 4H).

Compound 438.(7S)-7-(tert-butyl)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.60 (s, 1H), 8.26-8.16 (m, 1H), 7.46(d, J=0.7 Hz, 1H), 7.41 (dd, J=8.3, 2.5 Hz, 1H), 7.31 (d, J=0.8 Hz, 1H),7.20 (d, J=0.8 Hz, 1H), 5.17 (s, 2H), 4.88 (t, J=5.8 Hz, 1H), 4.35 (d,J=5.8 Hz, 2H), 3.61 (s, 1H), 3.12 (s, 3H), 2.14 (s, 3H), 0.92 (s, 9H).

Compound 443.(7S)-7-(2-hydroxyethyl)-4,5,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 Hz, Chloroform-d) δ 7.45 (s, 1H), 6.94 (brs, 1H), 5.46 (s,2H), 4.60 (t, J=5.0 Hz, 1H), 4.26 (dd, J=6.1, 2.3 Hz, 2H), 4.07 (dd,J=7.7, 5.8 Hz, 1H), 3.43-3.31 (m, 1H), 3.17 (s, 3H), 2.99 (s, 3H), 2.27(s, 3H), 1.79-1.32 (m, 2H).

Compound 445.(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-(2-hydroxyethyl)-4,5,8-trimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 8.31 (d, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.68(dd, J=8.3, 2.5 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.41 (s, 1H), 6.84 (t,J=6.0 Hz, 1H), 5.32 (s, 2H), 4.64-4.54 (m, 1H), 4.23 (dd, J=6.0, 2.3 Hz,2H), 4.04 (dd, J=7.7, 5.8 Hz, 1H), 3.17 (s, 3H), 2.97 (s, 3H), 2.25 (s,3H), 1.76-1.38 (m, 2H).

Compound 446.(7S)-2-(((1-((2-chloropyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 8.35 (dd, J=5.2, 0.7 Hz, 1H), 7.87 (s, 1H),7.59 (d, J=0.7 Hz, 1H), 7.43 (d, J=0.8 Hz, 1H), 7.06 (dq, J=1.6, 0.8 Hz,1H), 6.97 (ddt, J=5.1, 1.5, 0.7 Hz, 1H), 5.28 (s, 2H), 4.86 (t, J=5.8Hz, 1H), 4.47 (d, J=5.8 Hz, 2H), 3.90 (d, J=4.4 Hz, 1H), 3.13 (s, 3H),2.25 (qd, J=7.0, 4.4 Hz, 1H), 2.20 (s, 3H), 1.31-1.17 (m, 1H), 1.08 (d,J=7.0 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H)

Compound 608.(S)-2-(((1-((2-chloropyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-cyclopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.35 (dd, J=5.1, 0.7 Hz, 1H), 8.07 (s,1H), 7.64-7.54 (m, 1H), 7.48-7.37 (m, 1H), 7.05 (dd, J=1.6, 0.8 Hz, 1H),6.97 (dd, J=5.2, 1.5 Hz, 1H), 5.28 (s, 2H), 4.89 (t, J=5.8 Hz, 1H),4.56-4.35 (m, 2H), 3.30 (d, J=9.0 Hz, 1H), 3.15 (s, 3H), 2.25 (s, 3H),1.09-0.94 (m, 1H), 0.77-0.43 (m, 4H).

Compound 499.(S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-((R)-1-methoxyethyl)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.30 (d, J=2.4 Hz, 1H),7.76-7.62 (m, 2H), 7.47 (d, J=8.2 Hz, 1H), 7.40 (s, 1H), 6.55 (t, J=6.0Hz, 1H), 5.31 (s, 2H), 4.23 (d, J=6.0 Hz, 2H), 3.91 (d, J=5.8 Hz, 1H),3.47 (p, J=6.3 Hz, 1H), 3.16 (s, 3H), 3.08 (s, 3H), 2.12 (s, 3H), 1.08(d, J=6.4 Hz, 3H).

Compound 491.(S)-2-(((1-((2-chlorothiazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.39 (s, 1H), 7.91 (br, 1H), 7.77 (s, 1H),7.66 (d, J=1.0 Hz, 1H), 7.47 (s, 1H), 5.53 (s, 2H), 4.34 (d, J=5.7 Hz,2H), 4.10 (d, J=4.0 Hz, 1H), 3.15 (s, 3H), 2.27-2.10 (m, 1H), 2.20 (s,3H), 0.99 (d, J=6.9 Hz, 3H), 0.77 (d, J=6.9 Hz, 3H).

Compound 517.(S)-7-isopropyl-2-(((1-((2-isopropyloxazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 9.30 (s, 1H), 7.49-7.37 (m, 2H), 7.35(t, J=1.0 Hz, 1H), 5.07 (d, J=1.0 Hz, 2H), 4.88 (t, J=5.7 Hz, 1H), 4.33(d, J=5.7 Hz, 2H), 3.78 (d, J=4.4 Hz, 1H), 3.03 (s, 3H), 3.02-2.87 (m,1H), 2.15 (s, 4H), 1.24 (d, J=7.0 Hz, 6H), 0.98 (d, J=7.0 Hz, 3H), 0.84(d, J=6.9 Hz, 3H).

Compound 513.(S)-7-ethyl-2-(((1-((2-isopropyloxazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.11-6.99 (m, 2H), 4.23-4.16 (m, 1H),4.14 (d, J=3.8 Hz, 1H), 4.09-3.97 (m, 1H), 3.48 (s, 2H), 3.26 (s, 3H),2.88-2.77 (m, 2H), 2.40-2.31 (m, 1H), 2.30 (s, 3H), 2.13-1.99 (m, 2H),1.10 (t, J=7.5 Hz, 3H), 1.07-0.97 (m, 1H), 0.88 (d, J=6.9 Hz, 3H).

Compound 550.(S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isobutyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.37 (s, 1H), 8.34-8.25 (m, 1H), 7.54(d, J=0.8 Hz, 1H), 7.50 (dd, J=8.2, 2.5 Hz, 1H), 7.39 (d, J=0.8 Hz, 1H),7.31 (dd, J=8.2, 0.7 Hz, 1H), 5.27 (s, 2H), 4.88 (t, J=5.7 Hz, 1H),4.50-4.37 (m, 2H), 4.01 (dd, J=7.6, 5.8 Hz, 1H), 3.06 (s, 3H), 2.23 (s,3H), 1.88-1.72 (m, 1H), 1.60 (ddd, J=8.1, 5.6, 1.9 Hz, 2H), 0.96 (dd,J=17.4, 6.5 Hz, 6H)

Example 2V

The examples in Table 20 were prepared by Method A procedure by reactionof Intermediates A-9 and B-# (See procedure for Compound 46)

TABLE 20 Comp. No. Ring A Int A Int B [α]_(D) M + 1 488

A-9 B-187 +31.76 c = 0.5 MeOH 473.33 489

A-9 B-188 +13.54 c = 0.5 MeOH 491.29 490

A-9 B-189 +20.18 c = 0.5 461.31

Compound 488.(S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.61 (s, 1H), 7.12-6.98 (m,2H), 5.39-5.27 (m, 2H), 4.65-4.51 (m, 2H), 4.11 (t, J=10.1 Hz, 1H), 3.90(s, 3H), 3.57 (s, 1H), 3.02 (s, 3H), 2.26-2.16 (m, 4H), 0.99 (d, J=6.9Hz, 3H), 0.74 (t, J=12.3 Hz, 3H).

Compound 489.(S)-7-isopropyl-4,8-dimethyl-2-(((1-(4-(trifluoromethoxy)benzyl)-1H-1,2,4-triazol-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.65 (s, 1H), 7.43-7.33 (m,4H), 5.41 (s, 2H), 4.64-4.47 (m, 2H), 4.12 (d, J=3.7 Hz, 1H), 3.03 (d,J=22.2 Hz, 3H), 2.29-2.21 (m, 3H), 2.21-2.14 (m, 1H), 1.00 (t, J=7.2 Hz,3H), 0.75 (dd, J=19.6, 6.8 Hz, 3H).

Compound 490.(S)-7-isopropyl-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-1,2,4-triazol-3-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 7.25(d, J=8.6 Hz, 1H), 5.38 (s, 1H), 4.61-4.52 (m, 2H), 4.13 (dd, J=10.1,6.9 Hz, 3H), 3.06 (s, 1H), 3.02 (s, 2H), 2.30 (s, 2H), 2.24 (d, J=6.8Hz, 3H), 1.02-0.99 (m, 3H), 0.78 (dd, J=16.0, 6.9 Hz, 3H).

Example 2W

Table 21 provides certain compounds that were prepared by Method Aprocedure by reaction of Intermediates A-9 and B-# (See procedure forCompound 46). ¹H NMR data for certain compounds are also provided.

TABLE 21 Comp. No. Ring A Int A Int B [α]_(D) M + 1 451

A-9 B-193 473.29 452

A-9 B-192 +24.9 c = 0.5 MeOH 461.36

Compound 451.(S)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.11 (s, 2H), 7.20-7.00 (m,2H), 5.54 (s, 2H), 4.71-4.48 (m, 2H), 4.14 (t, J=17.3 Hz, 1H), 3.87 (d,J=27.8 Hz, 3H), 3.12 (s, 3H), 2.31-2.13 (m, 4H), 1.05 (t, J=31.1 Hz,3H), 0.75 (d, J=6.9 Hz, 3H).

Compound 452.(S)-7-isopropyl-4,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.13 (s, 1H), 7.29 (dd,J=8.5, 6.8 Hz, 2H), 5.56 (d, J=19.2 Hz, 2H), 4.77-4.46 (m, 2H), 4.12 (t,J=27.2 Hz, 2H), 3.36-2.92 (m, 4H), 2.37-1.91 (m, 4H), 1.05 (t, J=31.4Hz, 3H), 0.76 (t, J=9.4 Hz, 2H).

Example 2X

Table 22 provides certain compounds that were prepared by Method Aprocedure by reaction of Intermediates A-9 and B-# (See procedure forCompound 46). ¹H NMR data are also provided for certain compounds.

TABLE 22 Comp. No. L₁-Ring A Int A Int B [α]_(D) M + 1 453

A-9 CA +45.3 c = 0.5 MeOH 487.2 508

A-9 CA +24.65 c = 1.0 MeOH 451.12

Compound 453.(S)-2-(((2,5-dimethyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrol-3-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.91-7.75 (m, 2H), 7.48-7.32 (m, 2H),5.94 (d, J=1.1 Hz, 1H), 4.33 (d, J=1.1 Hz, 2H), 3.91 (d, J=4.5 Hz, 1H),3.35 (s, 1H), 3.17 (s, 3H), 2.16 (s, 4H), 2.01 (d, J=7.9 Hz, 6H), 1.04(d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 508.(S)-2-(((1-(4-fluorobenzyl)-2,5-dimethyl-1H-pyrrol-3-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.11-6.69 (m, 4H), 5.83 (d, J=1.0 Hz,1H), 5.02 (d, J=1.2 Hz, 3H), 4.28 (d, J=2.1 Hz, 2H), 3.90 (d, J=4.5 Hz,1H), 3.35-3.32 (m, 2H), 3.16 (s, 3H), 2.35-1.98 (m, 9H), 1.03 (d, J=7.0Hz, 3H), 0.88 (d, J=6.9 Hz, 3H). Scheme for synthesis of Compound 430.

Compound 430.(7S)-2-(((1-((6-fluoro-2-isopropylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)(methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared in two steps.

Step 1.(7S)-2-(((1-((6-fluoro-2-(prop-1-en-2-yl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)(methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

This compound was prepared by the general procedure (Method B; seeCompound 46) via reaction of A-9 and B-208 to provide the title productthat was used without further purification. ESI-MS m/z 465.39(M+1)⁺.

Step 2.(7S)-2-(((1-((6-fluoro-2-isopropylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)(methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

In a flask was placed the product from Step 1 (95 mg, 0.186 mmol) and10% Pd/C (50 mg) in 10 ml of methanol and charged with a hydrogenballoon. The reaction was stirred at room temperature for 14 hours. Thereaction was filtered through celite and the filtrate evaporated. Thecrude product was purified by column chromatography (SiO₂, 40 g) elutingwith a gradient of 0-20% methanol in dichloromethane. The desiredfractions were collected to provide the title product (52 mg, 57%yield). 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.67-7.51 (m, 2H),7.38 (d, J=0.7 Hz, 1H), 6.93 (dd, J=8.3, 3.5 Hz, 1H), 6.51 (t, J=6.0 Hz,1H), 5.35 (s, 2H), 4.21 (d, J=6.1 Hz, 2H), 3.84 (d, J=4.6 Hz, 1H),3.49-3.19 (m, 2H), 3.01 (s, 3H), 2.09 (s, 3H), 1.04 (d, J=6.6 Hz, 6H),0.93 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H). ESI-MS m/z calc.466.2605, found 467.51 (M+1)⁺; [α]_(D)=+8 6 0.86 (c=1, MeOH). ChiralHPLC (ChiralPAK IC column, 5×250 mm; 50% hexanes/30% ethanol/20%methanol (0.1% diethylamine) Rt 6.202 mins (96% ee).

Example 2Y General Scheme and Procedure for Examples in Table 23

Step 1:tert-Butyl-3-2-isopropyl-1,5-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-7-yl)amino)azetidine-1-carboxylate

(7S)-2-Chloro-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one (6.6 g,25.91 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (4.9 g, 28.45mmol) were taken into t-butanol (70 mL) and THE (65 mL). Sodiumtert-butoxide (12.5 g, 130 mmol) was added to the solution and themixture was degassed for 20 mins. by bubbling nitrogen in the solution.tButylXPhos palladacycle (Gen 1; 900 mg, 1.3 mmol) was added to themixture and heated for 1.5 hours at 50° C. The reaction was quenchedwith saturated ammonium chloride (80 ml) and extracted with ethylacetate 3×100 ml). The organic layer was collected combined and Pdscavenger (2 g) was added and stirred overnight at room temperature. Themixture was filtered and the solvent evaporated in vacuo. The resultingmaterial was triturated with 5% dichloromethane/methyl t-butyl ether (25ml), filtered and dried under vacuum at 40° C. to afford the titleproduct (9.7 g, 95% yield). ¹H NMR (400 MHz, Methanol-d4) δ 4.56 (tt,J=7.6, 5.5 Hz, 1H), 4.20 (dd, J=13.4, 8.1 Hz, 2H), 3.91 (d, J=4.4 Hz,1H), 3.86 (dd, J=8.6, 5.4 Hz, 2H), 3.12 (s, 3H), 2.21 (tt, J=10.0, 2.7Hz, 1H), 2.16 (s, 3H), 1.44 (s, 9H), 1.03 (d, J=7.0 Hz, 3H), 0.86 (d,J=6.9 Hz, 3H). ESMS (M+1)=391.26.

Step 2:(S)-7-(azetidin-3-ylamino)-2-isopropyl-1,5-dimethyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one

tert-Butyl(S)-3-((2-isopropyl-1,5-dimethyl-3-oxo-1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-7-yl)amino)azetidine-1-carboxylate(7.36 g, 18.42 mmol) was dissolved in 20 ml of dichloromethane.Trifluoroacetic acid (10 ml) was added to the solution and stirred atroom temperature for 14 hours. The reaction was concentrated to give aresidue that was dissolved in dichloromethane (30 ml) and triturated byslow addition of diethyl ether. The precipitate was collected byfiltration and dried in a vacuum oven at 50° C. to afford the titleproduct as a TFA salt (9 g, 98% yield). 1H NMR (400 MHz, Methanol-d4) δ5.01 (p, J=7.6 Hz, 1H), 4.46-4.31 (m, 2H), 4.19 (ddd, J=16.9, 10.2, 5.6Hz, 3H), 3.26 (s, 3H), 2.40-2.24 (m, 4H), 1.11 (d, J=7.0 Hz, 3H), 0.89(d, J=6.9 Hz, 3H). ESI-MS m/z calc. 290.18552, found 291.26 (M+1)⁺.

Step 3: Procedure for formation of amide derivatives in table below

To a solution of(7S)-2-(azetidin-3-ylamino)-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one(bis TFA salt) (50 mg, 0.1 mmol), the carboxylic acid (0.1 mmol), andHATU (55 mg, 0.15 mmol) in NMP (1 mL) at room temperature was addedDIPEA (67 mL, 0.4 mmol). The reaction was allowed to stir for 2 hours atroom temperature. The reaction mixture was diluted to 2 mL total volumewith DMSO and submitted for automated purification (Ortho 2 method). Thesolvent was removed under reduced pressure to afford the amide.

Table 23 provides certain compounds that were prepared via the generalprocedure reported above. ¹H NMR data are also provided for certaincompounds.

TABLE 23 Comp. No. Ring B [α]_(D) M + 1 496

+95.95 c = 1.05 MeOH 449.33 542

461.26 543

437.31 544

463.24 545

464.28 548

413.27 549

430.25 594

477.87 595

466.87 596

467.3 597

467.3 605

386.26 606

423.35 607

477.92 609

467.3 610

400.33 611

403.36 612

493.3 613

470.27 614

435.36 615

494.36 616

445.33 617

387.27 618

427.31 619

428.37 620

400.33 621

453.31 622

463.34 623

427.38 626

445.26 627

423.35 628

445.28 629

445.33 630

436.22 631

397.36 632

445.33 633

436.29 634

439.39 635

463.34 636

389.38 637

403.36 638

403.36 639

413.39 640

397.29 641

423.35 642

389.38 643

453.3

Compound 496.(S)-7-isopropyl-4,8-dimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.47 (dd, J=8.2, 6.7 Hz, 2H), 4.76-4.62(m, 2H), 4.55-4.42 (m, 1H), 4.39-4.28 (m, 1H), 4.17-4.06 (m, 1H), 3.92(d, J=4.4 Hz, 1H), 3.11 (s, 3H), 2.28-2.17 (m, 1H), 2.16 (s, 3H), 1.02(d, J=7.0 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H).

Compound 542.(S)-2-((1-(3,5-difluoro-4-methoxybenzoyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.37-7.25 (m, 2H), 4.74-4.61 (m, 2H),4.46 (s, 1H), 4.35 (s, 1H), 4.11 (d, J=7.2 Hz, 1H), 4.03 (s, 3H), 3.93(d, J=4.4 Hz, 1H), 3.12 (s, 3H), 2.29-2.19 (m, 1H), 2.17 (s, 3H), 1.03(d, J=7.0 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H).

Compound 543.(S)-2-((1-(4,4-difluorocyclohexane-1-carbonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 4.66 (ddd, J=12.9, 7.6, 5.3 Hz, 1H),4.57 (td, J=8.3, 4.8 Hz, 1H), 4.32-4.23 (m, 1H), 4.18 (td, J=8.9, 5.3Hz, 1H), 3.98 (d, J=4.2 Hz, 1H), 3.93 (dd, J=10.3, 5.4 Hz, 1H), 3.16 (s,3H), 2.43 (t, J=9.7 Hz, 1H), 2.24 (ddd, J=9.8, 9.3, 4.9 Hz, 1H), 2.20(s, 3H), 2.09 (d, J=7.7 Hz, 2H), 1.93-1.66 (m, 6H), 1.05 (d, J=7.0 Hz,3H), 0.87 (d, J=6.9 Hz, 3H).

Compound 544.(S)-7-isopropyl-4,8-dimethyl-2-((1-(2-(3,4,5-trifluorophenyl)acetyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.11-7.01 (m, 2H), 4.67 (dq, J=7.3, 5.4Hz, 1H), 4.58 (td, J=8.3, 4.4 Hz, 1H), 4.36-4.27 (m, 1H), 4.25-4.16 (m,1H), 4.02-3.92 (m, 2H), 3.52 (s, 2H), 3.14 (d, J=5.0 Hz, 3H), 2.24 (tdd,J=6.9, 5.7, 1.9 Hz, 1H), 2.20 (s, 3H), 1.05 (d, J=7.0 Hz, 3H), 0.87 (d,J=6.9 Hz, 3H).

Compound 545.(S)-7-isopropyl-4,8-dimethyl-2-((1-(6-(trifluoromethyl)nicotinoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J=1.5 Hz, 1H), 8.29 (dd, J=8.1,1.7 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 4.83-4.63 (m, 6H), 4.59-4.51 (m,1H), 4.38 (dd, J=14.0, 8.8 Hz, 1H), 4.20 (dd, J=10.7, 5.3 Hz, 1H), 3.98(d, J=4.2 Hz, 1H), 3.15 (s, 3H), 2.32-2.21 (m, 1H), 2.20 (s, 3H), 1.04(d, J=7.0 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H).

Compound 548.(S)-2-((1-(4-fluorobenzoyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.72 (dd, J=8.6, 5.5 Hz, 2H), 7.19 (t,J=8.7 Hz, 2H), 4.77-4.58 (m, 2H), 4.55-4.41 (m, 1H), 4.33 (d, J=5.1 Hz,1H), 4.14 (dd, J=10.4, 4.8 Hz, 1H), 3.94 (d, J=4.3 Hz, 1H), 3.12 (s,3H), 2.28-2.19 (m, 1H), 2.18 (s, 3H), 1.03 (d, J=6.9 Hz, 3H), 0.86 (d,J=6.9 Hz, 3H).

Compound 549.(S)-2-((1-(6-chloronicotinoyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.66 (d, J=2.1 Hz, 1H), 8.07 (dd, J=8.3,2.3 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 4.80-4.63 (m, 2H), 4.51 (dd,J=14.5, 8.6 Hz, 1H), 4.44-4.29 (m, 1H), 4.16 (dd, J=10.5, 4.9 Hz, 1H),3.97 (d, J=4.2 Hz, 1H), 3.14 (s, 3H), 2.30-2.21 (m, 1H), 2.19 (s, 3H),1.04 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H).

Compound 594.(S)-7-isopropyl-4,8-dimethyl-2-((1-(2-(6-(trifluoromethyl)pyridin-3-yl)acetyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.62 (s, 1H), 7.94 (d, J=8.3Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.16 (s, 1H), 4.51 (s, 2H), 4.10 (d,J=7.5 Hz, 2H), 3.90 (s, 1H), 3.81 (s, 1H), 3.63 (s, 2H), 3.06-2.95 (m,3H), 2.12 (s, 4H), 0.95 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 595.(S)-7-isopropyl-4,8-dimethyl-2-((1-(2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.91 (s, 1H), 7.18 (s, 1H),6.74 (s, 1H), 5.11-4.92 (m, 2H), 4.53 (s, 1H), 4.41 (t, J=7.4 Hz, 1H),4.16 (t, J=8.1 Hz, 1H), 4.01 (s, 1H), 3.89 (dd, J=15.7, 4.6 Hz, 2H),3.02 (m, 3H), 2.13 (s, 4H), 0.95 (d, J=6.8 Hz, 3H), 0.77 (d, J=6.8 Hz,3H).

Compound 596.(S)-7-isopropyl-4,8-dimethyl-2-((1-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.13 (s, 1H), 7.04 (t, J=5.8Hz, 1H), 4.67-4.49 (m, 2H), 4.36-4.14 (m, 2H), 4.08 (s, 2H), 4.05-3.96(m, 1H), 3.87 (d, J=4.3 Hz, 1H), 3.02 (s, 3H), 2.11 (s, 3H), 0.94 (d,J=6.8 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 597.(S)-7-isopropyl-4,8-dimethyl-2-((1-(1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.21 (s, 1H), 7.13 (s, 1H),4.72 (t, J=7.8 Hz, 1H), 4.56 (d, J=5.5 Hz, 1H), 4.45-4.19 (m, 2H), 4.02(s, 3H), 3.98-3.81 (m, 2H), 3.03 (s, 3H), 2.12 (s, 4H), 0.94 (d, J=4.7Hz, 3H), 0.77 (d, J=6.7 Hz, 3H).

Compound 605.(S)-7-isopropyl-4,8-dimethyl-2-((1-(oxazole-4-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H),7.08 (d, J=5.5 Hz, 1H), 4.71 (dd, J=11.9, 5.0 Hz, 1H), 4.54 (s, 1H),4.29 (ddd, J=29.4, 15.3, 8.7 Hz, 2H), 4.04-3.80 (m, 2H), 3.00 (d, J=7.0Hz, 3H), 2.11 (s, 4H), 0.94 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 606.(S)-2-((1-(2-(3,3-difluorocyclobutyl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 6.99 (d, J=6.1 Hz, 1H),4.54-4.38 (m, 1H), 4.33 (td, J=7.9, 3.3 Hz, 1H), 4.04 (t, J=7.6 Hz, 1H),3.97-3.81 (m, 2H), 3.81-3.66 (m, 1H), 3.01 (s, 3H), 2.77-2.58 (m, 2H),2.46-2.16 (m, 5H), 2.16-2.03 (m, 4H), 0.93 (d, J=6.9 Hz, 3H), 0.75 (d,J=6.9 Hz, 3H).

Compound 607.(S)-7-isopropyl-4,8-dimethyl-2-((1-(6-(trifluoromethoxy)nicotinoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.61 (d, J=1.8 Hz, 1H), 8.23(dd, J=8.5, 2.3 Hz, 1H), 7.36 (d, J=8.6 Hz, 1H), 7.04 (s, 1H), 4.58 (dd,J=19.2, 11.1 Hz, 2H), 4.31 (t, J=7.2 Hz, 1H), 4.25-4.14 (m, 1H), 4.01(dd, J=10.0, 5.1 Hz, 1H), 3.87 (d, J=4.3 Hz, 1H), 3.01 (s, 3H), 2.11 (d,J=12.7 Hz, 4H), 0.93 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H).

Compound 609.(S)-7-isopropyl-4,8-dimethyl-2-((1-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.31 (s, 1H), 7.07 (s, 1H),4.49 (dd, J=16.4, 8.5 Hz, 2H), 4.20 (s, 1H), 4.08 (d, J=13.4 Hz, 1H),3.99-3.82 (m, 4H), 3.01 (s, 3H), 2.12 (d, J=11.6 Hz, 4H), 0.94 (d, J=6.9Hz, 3H), 0.75 (d, J=6.9 Hz, 3H).

Compound 610.(S)-7-isopropyl-4,8-dimethyl-2-((1-(2-methyloxazole-4-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.46 (s, 1H), 7.06 (d, J=5.4Hz, 1H), 4.69 (t, J=7.3 Hz, 1H), 4.63-4.44 (m, 1H), 4.37-4.13 (m, 2H),3.89 (dd, J=14.6, 5.2 Hz, 2H), 3.01 (s, 3H), 2.43 (s, 3H), 2.12 (d,J=11.1 Hz, 4H), 0.94 (d, J=6.8 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 611.(7S)-7-isopropyl-4,8-dimethyl-2-((1-(tetrahydro-2H-pyran-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.01 (dd, J=10.8, 5.2 Hz, 1H),4.55-4.33 (m, 2H), 4.16-3.96 (m, 2H), 3.87 (d, J=4.2 Hz, 2H), 3.79-3.66(m, 1H), 3.01 (s, 3H), 2.10 (s, 4H), 1.76 (s, 1H), 1.64 (d, J=6.6 Hz,1H), 1.47 (d, J=8.9 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.8 Hz,3H).

Compound 612.(S)-7-isopropyl-4,8-dimethyl-2-((1-(2-(2-(trifluoromethyl)phenoxy)acetyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.61 (t, J=8.2 Hz, 2H),7.18-6.96 (m, 3H), 4.77 (s, 2H), 4.58-4.38 (m, 2H), 4.15 (t, J=8.4 Hz,1H), 4.02 (d, J=3.0 Hz, 1H), 3.85 (dd, J=13.8, 4.7 Hz, 2H), 3.00 (s,3H), 2.11 (d, J=11.9 Hz, 4H), 0.93 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.9 Hz,3H).

Compound 613.(S)-7-isopropyl-4,8-dimethyl-2-((1-(2-(trifluoromethyl)thiazole-4-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.69 (s, 1H), 7.05 (d, J=5.9Hz, 1H), 4.82-4.66 (m, 1H), 4.54 (d, J=7.0 Hz, 1H), 4.44-4.25 (m, 2H),3.97 (dd, J=14.7, 9.6 Hz, 1H), 3.86 (d, J=4.5 Hz, 1H), 3.00 (d, J=4.3Hz, 3H), 2.22-1.97 (m, 4H), 0.93 (d, J=6.3 Hz, 3H), 0.81-0.68 (m, 3H).

Compound 614.(S)-2-((1-(1-(difluoromethyl)-1H-pyrazole-3-carbonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.33 (d, J=2.4 Hz, 1H), 7.87(t, J=58.9 Hz, 2H), 7.07 (d, J=5.5 Hz, 1H), 6.85 (d, J=2.6 Hz, 1H), 4.70(t, J=7.7 Hz, 1H), 4.64-4.46 (m, 1H), 4.43-4.19 (m, 2H), 4.02-3.81 (m,2H), 3.01 (s, 3H), 2.22-2.00 (m, 4H), 0.94 (dd, J=6.8, 2.1 Hz, 3H), 0.76(d, J=6.1 Hz, 3H).

Compound 615.(S)-7-isopropyl-4,8-dimethyl-2-((1-(6-(2,2,2-trifluoroethoxy)nicotinoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.48 (d, J=1.7 Hz, 1H), 8.03(dd, J=8.6, 2.3 Hz, 2H), 7.11-6.95 (m, 3H), 5.05 (dd, J=18.1, 9.0 Hz,2H), 4.58 (d, J=9.0 Hz, 3H), 4.28 (s, 1H), 4.19 (s, 1H), 4.04-3.94 (m,2H), 3.87 (d, J=4.3 Hz, 1H), 3.00 (d, J=3.9 Hz, 4H), 2.11 (d, J=12.9 Hz,4H), 0.93 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.8 Hz, 3H).

Compound 616.(S)-2-((1-(2-(2,4-difluorophenyl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.33 (dd, J=15.5, 8.5 Hz, 1H),7.19 (td, J=10.1, 2.5 Hz, 1H), 7.03 (t, J=7.6 Hz, 2H), 4.59-4.33 (m,2H), 4.16-3.97 (m, 2H), 3.93-3.70 (m, 2H), 3.45 (s, 2H), 3.02 (s, 3H),2.12 (d, J=12.1 Hz, 4H), 0.94 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9 Hz, 3H).

Compound 617.(S)-2-((1-(1,2,5-oxadiazole-3-carbonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.05 (d, J=5.5 Hz, 1H),4.63-4.44 (m, 2H), 4.22 (dt, J=12.8, 8.3 Hz, 2H), 3.89 (dd, J=10.2, 4.8Hz, 2H), 3.00 (d, J=4.2 Hz, 3H), 2.12 (d, J=13.0 Hz, 4H), 0.93 (d, J=6.9Hz, 3H), 0.75 (d, J=6.9 Hz, 3H).

Compound 618.(S)-2-((1-(2-(4-fluorophenyl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.26 (dd, J=8.3, 5.8 Hz, 2H),7.11 (t, J=8.8 Hz, 2H), 7.02 (d, J=5.8 Hz, 1H), 4.44 (ddd, J=15.3, 12.1,6.6 Hz, 2H), 4.14-3.93 (m, 2H), 3.87 (d, J=4.4 Hz, 1H), 3.77 (td, J=9.4,5.3 Hz, 1H), 3.41 (s, 2H), 3.00 (d, J=2.5 Hz, 3H), 2.12 (d, J=15.1 Hz,4H), 0.94 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.9 Hz, 3H).

Compound 619.(S)-7-isopropyl-2-((1-(5-isopropylisoxazole-3-carbonyl)azetidin-3-yl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.07 (d, J=6.0 Hz, 1H), 6.53(s, 1H), 4.72-4.49 (m, 2H), 4.37-4.22 (m, 2H), 4.04-3.83 (m, 2H), 3.14(td, J=14.0, 7.1 Hz, 1H), 3.00 (d, J=5.0 Hz, 3H), 2.11 (s, 4H), 1.26 (d,J=6.9 Hz, 6H), 0.94 (dd, J=6.8, 2.0 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 620.(S)-7-isopropyl-4,8-dimethyl-2-((1-(3-methylisoxazole-5-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.08 (d, J=6.0 Hz, 1H), 6.89(s, 1H), 4.69 (dd, J=11.1, 5.3 Hz, 1H), 4.64-4.52 (m, 1H), 4.31 (dd,J=16.7, 9.1 Hz, 2H), 3.96 (dd, J=10.1, 5.1 Hz, 1H), 3.87 (d, J=4.4 Hz,1H), 3.01 (s, 3H), 2.29 (s, 3H), 2.11 (s, 4H), 0.94 (d, J=5.8 Hz, 3H),0.76 (d, J=6.6 Hz, 3H).

Compound 621.(S)-7-isopropyl-4,8-dimethyl-2-((1-(5-(trifluoromethyl)furan-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.21(d, J=3.2 Hz, 2H), 4.71 (d, J=5.0 Hz, 1H), 4.61 (s, 1H), 4.45-4.24 (m,2H), 4.08-3.85 (m, 2H), 3.03 (s, 3H), 2.12 (d, J=11.6 Hz, 4H), 0.94 (d,J=6.7 Hz, 3H), 0.76 (d, J=6.6 Hz, 3H).

Compound 622.(S)-7-isopropyl-4,8-dimethyl-2-((1-(4-(trifluoromethyl)benzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 7.83 (s, 3H), 7.27 (s, 1H),4.65-4.46 (m, 2H), 4.33 (s, 1H), 4.18 (s, 1H), 4.09-3.99 (m, 1H), 3.92(d, J=3.4 Hz, 1H), 3.03 (s, 3H), 2.13 (s, 4H), 0.94 (d, J=6.8 Hz, 3H),0.75 (d, J=6.9 Hz, 3H).

Compound 623.(7S)-2-((1-(2-(bicyclo[2.2.1]heptan-2-yl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.14 (s, 1H), 4.46 (d, J=5.7Hz, 1H), 4.32 (td, J=7.9, 3.6 Hz, 1H), 4.05 (t, J=8.7 Hz, 1H), 4.01-3.86(m, 2H), 3.82-3.69 (m, 1H), 3.03 (s, 3H), 2.13 (d, J=10.8 Hz, 5H),2.07-1.69 (m, 5H), 1.52-1.24 (m, 4H), 1.21-0.87 (m, 7H), 0.75 (d, J=6.9Hz, 3H).

Compound 626.(S)-2-((1-(2-(3,4-difluorophenyl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.32 (ddd, J=16.5, 15.8, 10.1Hz, 2H), 7.13-6.98 (m, 2H), 4.57-4.37 (m, 2H), 4.15-3.94 (m, 2H), 3.87(d, J=4.4 Hz, 1H), 3.78 (td, J=9.5, 5.1 Hz, 1H), 3.43 (s, 2H), 3.00 (t,J=2.6 Hz, 3H), 2.24-1.96 (m, 4H), 0.94 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9Hz, 3H).

Compound 627.(S)-7-isopropyl-4,8-dimethyl-2-((1-((R)-2-phenylpropanoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.90 (d, J=4.5 Hz, 1H), 7.38-7.16 (m, 4H),6.97 (dd, J=19.8, 5.8 Hz, 1H), 4.54-4.37 (m, 1H), 4.35 (dd, J=13.0, 6.6Hz, 1H), 4.07 (t, J=6.7 Hz, 1H), 4.03-3.91 (m, 1H), 3.90-3.60 (m, 3H),2.97 (d, J=18.1 Hz, 3H), 2.08 (d, J=6.7 Hz, 4H), 1.26 (d, J=6.9 Hz, 3H),0.93 (dd, J=6.7, 4.2 Hz, 3H), 0.74 (t, J=7.1 Hz, 3H).

Compound 628.(S)-2-((1-(2-(2,5-dimethylthiazol-4-yl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.04 (d, J=3.9 Hz, 1H), 4.42(ddd, J=13.0, 9.7, 5.6 Hz, 2H), 4.12-3.92 (m, 2H), 3.88 (d, J=4.3 Hz,1H), 3.76 (dd, J=15.6, 6.4 Hz, 1H), 3.42 (s, 2H), 3.02 (s, 3H), 2.29 (s,3H), 2.12 (d, J=12.8 Hz, 4H), 0.94 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9 Hz,3H).

Compound 629.(S)-2-((1-(2-(3,5-difluorophenyl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.23-6.82 (m, 3H), 4.57-4.35(m, 2H), 4.18-3.98 (m, 2H), 3.80 (ddd, J=18.1, 14.3, 4.8 Hz, 2H), 3.00(d, J=5.8 Hz, 3H), 2.24-1.98 (m, 4H), 0.93 (d, J=6.9 Hz, 3H), 0.76 (d,J=6.9 Hz, 3H).

Compound 630.(S)-2-((1-(2-chlorothiazole-4-carbonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.28 (s, 1H), 7.11 (s, 1H),4.72 (t, J=8.6 Hz, 1H), 4.63-4.49 (m, 1H), 4.44-4.20 (m, 2H), 4.02-3.83(m, 2H), 3.02 (s, 3H), 2.13 (d, J=9.7 Hz, 4H), 0.94 (d, J=6.4 Hz, 3H),0.76 (d, J=6.8 Hz, 3H).

Compound 631.(S)-7-isopropyl-4,8-dimethyl-2-((1-(pyrazine-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.11 (s, 1H), 8.79 (d, J=1.1Hz, 1H), 8.70 (d, J=1.4 Hz, 1H), 7.08 (d, J=5.6 Hz, 1H), 4.79 (t, J=8.7Hz, 1H), 4.64-4.48 (m, 1H), 4.48-4.24 (m, 2H), 4.08-3.95 (m, 1H), 3.87(d, J=4.4 Hz, 1H), 3.01 (s, 3H), 2.11 (s, 4H), 0.93 (dd, J=6.8, 2.4 Hz,3H), 0.76 (d, J=5.8 Hz, 3H).

Compound 632.(S)-2-((1-(2-(2,3-difluorophenyl)acetyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 7.31 (dd, J=16.2, 8.2 Hz, 1H),7.22-6.96 (m, 2H), 4.45 (dd, J=11.0, 7.4 Hz, 2H), 4.17-3.98 (m, 2H),3.89-3.74 (m, 2H), 3.54 (s, 2H), 3.02 (s, 3H), 2.12 (d, J=12.0 Hz, 4H),0.94 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.9 Hz, 3H).

Compound 633.(S)-2-((1-(2-chlorothiazole-5-carbonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.04 (s, 1H), 7.08 (s, 1H),4.71 (d, J=6.7 Hz, 1H), 4.61 (s, 1H), 4.30 (d, J=9.0 Hz, 2H), 4.01 (s,1H), 3.87 (d, J=4.4 Hz, 1H), 3.01 (s, 3H), 2.12 (d, J=10.2 Hz, 4H), 0.93(d, J=6.7 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 634.(S)-7-isopropyl-2-((1-((R)-2-methoxy-2-phenylacetyl)azetidin-3-yl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.45-7.23 (m, 4H), 7.02 (dd,J=8.9, 6.0 Hz, 1H), 4.79 (d, J=3.4 Hz, 1H), 4.59-4.33 (m, 2H), 4.21-3.99(m, 2H), 3.99-3.73 (m, 2H), 3.28 (s, 3H), 2.98 (d, J=10.0 Hz, 3H), 2.09(d, J=2.8 Hz, 4H), 0.93 (d, J=6.8 Hz, 3H), 0.75 (dd, J=6.8, 2.4 Hz, 3H).

Compound 635.(S)-7-isopropyl-4,8-dimethyl-2-((1-(3-(trifluoromethyl)benzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 7.90 (t, J=8.2 Hz, 2H), 7.70(t, J=7.8 Hz, 1H), 7.04 (d, J=4.0 Hz, 1H), 4.54 (s, 2H), 4.31 (s, 1H),4.17 (s, 1H), 3.99 (s, 1H), 3.87 (d, J=4.3 Hz, 1H), 3.00 (d, J=3.2 Hz,3H), 2.11 (d, J=11.8 Hz, 4H), 0.93 (d, J=6.8 Hz, 3H), 0.75 (d, J=6.9 Hz,3H).

Compound 636.(S)-7-isopropyl-4,8-dimethyl-2-((1-((R)-tetrahydrofuran-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 7.00 (d, J=5.1 Hz, 1H), 4.44(dd, J=17.0, 8.1 Hz, 2H), 4.31 (dd, J=13.0, 5.7 Hz, 1H), 4.07 (dd,J=19.7, 12.9 Hz, 2H), 3.87 (d, J=4.4 Hz, 1H), 3.82-3.61 (m, 3H), 3.01(s, 3H), 2.22-1.68 (m, 9H), 0.93 (d, J=6.9 Hz, 3H), 0.75 (d, J=6.9 Hz,3H).

Compound 637.(7S)-7-isopropyl-4,8-dimethyl-2-((1-(5-methyltetrahydrofuran-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 7.11 (s, 1H), 4.47 (s, 2H),4.26 (dd, J=13.1, 6.2 Hz, 1H), 4.09 (s, 2H), 3.99-3.85 (m, 2H), 3.77(dd, J=9.7, 5.2 Hz, 1H), 3.03 (s, 3H), 2.23-1.81 (m, 8H), 1.39 (ddd,J=20.4, 15.1, 8.5 Hz, 1H), 1.25-1.07 (m, 3H), 0.94 (d, J=6.9 Hz, 3H),0.76 (d, J=6.9 Hz, 3H).

Compound 638.(7S)-7-isopropyl-4,8-dimethyl-2-((1-(2-methyltetrahydrofuran-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.08 (s, 1H), 4.64-4.40 (m,2H), 4.12 (ddd, J=26.6, 13.0, 7.1 Hz, 2H), 3.95-3.58 (m, 4H), 3.03 (s,3H), 2.29 (dd, J=11.8, 5.2 Hz, 1H), 2.13 (d, J=13.2 Hz, 4H), 1.91-1.67(m, 2H), 1.67-1.53 (m, 1H), 1.29 (d, J=3.1 Hz, 3H), 0.94 (d, J=6.9 Hz,3H), 0.76 (d, J=6.9 Hz, 3H).

Compound 639.(7S)-2-((1-(bicyclo[2.2.1]heptane-2-carbonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.05 (d, J=17.3 Hz, 1H),4.57-4.27 (m, 2H), 4.17-3.64 (m, 5H), 3.02 (d, J=2.4 Hz, 3H), 2.66 (t,J=11.8 Hz, 1H), 2.44-2.34 (m, 1H), 2.14 (d, J=22.1 Hz, 5H), 1.69-1.08(m, 9H), 0.94 (d, J=6.9 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 640.(S)-7-isopropyl-4,8-dimethyl-2-((1-(pyrimidine-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.92 (dd, J=4.9, 1.7 Hz, 1H),7.62 (td, J=4.9, 1.3 Hz, 1H), 7.08 (d, J=4.9 Hz, 1H), 4.56 (dt, J=12.4,6.6 Hz, 2H), 4.37-4.15 (m, 2H), 4.04-3.93 (m, 1H), 3.87 (d, J=4.3 Hz,1H), 3.01 (s, 3H), 2.12 (d, J=11.6 Hz, 4H), 0.93 (d, J=6.2 Hz, 3H), 0.75(d, J=6.9 Hz, 3H).

Compound 641.(S)-7-isopropyl-4,8-dimethyl-2-((1-((S)-2-phenylpropanoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.93 (d, J=7.8 Hz, 1H), 7.38-7.14 (m, 4H),7.02 (d, J=19.7 Hz, 1H), 4.54-4.38 (m, 1H), 4.34 (dd, J=13.2, 6.5 Hz,1H), 4.04 (dt, J=17.6, 9.2 Hz, 2H), 3.84 (ddd, J=15.3, 8.9, 5.1 Hz, 2H),3.68 (dt, J=13.8, 6.1 Hz, 2H), 2.98 (d, J=12.2 Hz, 3H), 2.09 (d, J=7.0Hz, 4H), 1.26 (dd, J=6.9, 2.3 Hz, 3H), 0.93 (dd, J=6.8, 3.1 Hz, 3H),0.75 (dd, J=6.7, 4.3 Hz, 3H).

Compound 642.(S)-7-isopropyl-4,8-dimethyl-2-((1-((S)-tetrahydrofuran-2-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.06 (s, 1H), 4.45 (d, J=5.6Hz, 2H), 4.30 (d, J=5.7 Hz, 1H), 4.20-4.03 (m, 2H), 3.88 (d, J=3.7 Hz,1H), 3.83-3.63 (m, 2H), 3.01 (d, J=10.2 Hz, 3H), 2.22-1.68 (m, 8H), 0.94(d, J=6.9 Hz, 3H), 0.76 (d, J=6.8 Hz, 3H).

Compound 699.(S)-7-isopropyl-4,8-dimethyl-2-((1-(3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbonyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 4.70-4.60 (m, 2H), 4.37-4.23 (m, 2H),4.03-3.94 (m, 1H), 3.92 (d, J=4.3 Hz, 1H), 3.12 (s, 3H), 2.29 (s, 6H),2.21 (dd, J=11.6, 6.8 Hz, 1H), 2.17 (s, 3H), 2.03 (s, 1H), 1.03 (d,J=6.9 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H).

Compound 592.(7S)-2-((1-((4-fluorophenyl)sulfonyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-7-(azetidin-3-ylamino)-2-isopropyl-1,5-dimethyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one(prepared in step 2 of scheme for Table H) (200 mg, 0.495 mmol) wastaken into dichloromethane (4 ml) and diisopropylethylamine (0.35 μL,1.98 mmol). 4-Fluorobenzenesulfonyl chloride (106 mg, 0.545 mmol) wasadded to the mixture and stirred at room temperature for 2 hours. Thereaction was quenched with 5 ml of saturated sodium bicarbonate andstirred for 30 mins. The layers were separated with phase separatorcartridge and the solvent removed under reduced pressure. The crudeproduct was purified by column chromatography (SiO₂, 80 g) eluting witha gradient of 0-20% methanol in dichloromethane. The desired fractionswere evaporated in vacuo to afford the title product (124 mg, 56%yield). 1H NMR (400 MHz, Methanol-d4) δ 7.98-7.88 (m, 2H), 7.39 (t,J=8.7 Hz, 2H), 4.51-4.37 (m, 1H), 4.09 (td, J=7.6, 4.3 Hz, 2H), 3.89 (d,J=4.4 Hz, 1H), 3.62 (dd, J=14.6, 6.4 Hz, 2H), 3.07 (s, 3H), 2.24-2.12(m, 1H), 2.11 (s, 3H), 1.01 (d, J=7.0 Hz, 3H), 0.83 (d, J=6.9 Hz, 3H).ESI-MS m/z calc. 448.16928, found 449.29 (M+1)⁺.

Compound 564.(7S)-3-((7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)-N-(3,4,5-trifluorophenyl)azetidine-1-carboxamide

1,2,3-trifluoro-5-isocyanatobenzene (38 mg, 0.22 mmol) was added to asolution of(7S)-7-(azetidin-3-ylamino)-2-isopropyl-1,5-dimethyl-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one(82 mg, 0.158 mmol) and diisopropylethylamine (0.14 μL, 0.79 mmol) inNMP (2 ml). The reaction was heated at 50° C. for 1 hour. The reactionwas purified by preparative reverse phase HPLC (C18 column; 10-90%acetonitrile/water (HCl). The relevant fraction were evaporated toprovide the title product as the hydrochloride salt (27 mg, 29% yield).1H NMR (400 MHz, Methanol-d4) δ 7.21 (dddd, J=10.2, 9.1, 3.9, 2.3 Hz,2H), 4.82-4.68 (m, 1H), 4.40-4.04 (m, 1H), 3.53-3.34 (m, 1H), 3.31-3.27(m, 3H), 3.23 (d, J=5.9 Hz, 1H), 2.33-2.24 (m, 3H), 1.14-0.77 (m, 6H).ESI-MS m/z calc. 463.19437, found 464.24 (M+1)⁺.

Example 2Z Reaction Scheme for Examples in Table 24

The following examples of Table 24 were prepared from variousIntermediates A-# via the general procedure reported for Table 23.

TABLE 24 Comp. No. R³ R⁴ Int A [α]_(D) M + 1 568 —(R)—CH(OCH₃)CH₃ H A-59465.27 675

H A-66 +96.7 c = 0.86 MeOH 491.2 721 —CH₂OCH₃ —CH₃ A-69 +37.6 465.28 c =0.76 MeOH 722 —CH₃ —CH₂OCH₃ A-70 −29.30 465.32 c = 0.86 MeOH 739 —Et HA-8  435.38 740 —CH₃ H A-2  435.38

Compound 568.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.52-7.41 (m, 2H), 4.76-4.60 (m, 2H),4.54-4.41 (m, 1H), 4.39-4.29 (m, 1H), 4.19-4.06 (m, 1H), 3.97 (d, J=5.4Hz, 1H), 3.64-3.52 (m, 1H), 3.26 (s, 3H), 3.17 (s, 3H), 2.18 (s, 3H),1.18 (d, J=6.4 Hz, 3H).

Compound 675.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 7.65-7.37 (m, 2H), 7.06 (s,1H), 4.71-4.47 (m, 2H), 4.42-4.12 (m, 3H), 4.02 (dt, J=12.2, 6.1 Hz,1H), 3.08 (d, J=14.3 Hz, 6H), 2.28-2.19 (m, 1H), 2.19-2.07 (m, 5H),2.04-1.84 (m, 1H), 1.70 (ddd, J=15.0, 9.6, 5.2 Hz, 1H), 1.64-1.45 (m,1H).

Compound 721.7-(methoxymethyl)-4,7,8-trimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 2H), 7.69-7.38 (m, 4H), 4.68 (s,5H), 4.34 (d, J=23.6 Hz, 5H), 4.09 (d, J=9.9 Hz, 2H), 3.67 (s, 4H), 3.22(s, 6H), 3.11 (s, 6H), 2.25 (s, 6H), 1.46 (s, 6H), 8.36-7.85 (m, 1H).

Compound 722.7-(methoxymethyl)-4,7,8-trimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 3.22 (s, 3H), 3.11 (s, 3H), 2.25 (s, 3H),1.46 (s, 3H), 3.72-3.60 (m, 2H), 10.50 (s, 1H), 8.10 (s, 1H), 7.69-7.21(m, 2H), 4.68 (s, 2H), 4.36 (s, 2H).

Compound 739.(S)-7-ethyl-4,8-dimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.51-7.41 (m, 2H), 4.76-4.59 (m, 2H),4.47 (s, 1H), 4.33 (s, 1H), 4.18-4.00 (m, 2H), 3.06 (s, 2H), 2.17 (s,2H), 1.99-1.74 (m, 2H), 0.84 (t, J=7.5 Hz, 3H).

Compound 740.(S)-4,7,8-trimethyl-2-((1-(3,4,5-trifluorobenzoyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.53-7.42 (m, 2H), 4.75-4.59 (m, 2H),4.47 (d, J=7.2 Hz, 1H), 4.32 (s, 1H), 4.18-4.00 (m, 2H), 3.04 (s, 3H),2.18 (s, 3H), 1.33 (d, J=6.9 Hz, 3H).

(7S)-7-Isopropyl-4,8-dimethyl-2-(((S)-1-(3,4,5-trifluorobenzoyl)pyrrolidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared via the same general 3 step procedure recordedfor Table H examples to provide the title compound. ¹H NMR (400 MHz,Methanol-d4) δ 7.37 (dt, J=14.3, 7.3 Hz, 2H), 4.63-4.53 (m, 0.5H),4.49-4.40 (m, 0.5H), 3.96 (dd, J=21.8, 4.3 Hz, 1.5H), 3.81 (ddd, J=28.9,12.9, 6.6 Hz, 1H), 3.66 (dt, J=11.7, 4.8 Hz, 1H), 3.63-3.53 (m, 1H),3.48 (dd, J=10.9, 4.7 Hz, 0.5H), 3.19 (s, 1.5H), 3.09 (s, 1.5H), 2.19(d, J=19.8 Hz, 5H), 2.13-1.95 (m, 1H), 1.03 (dd, J=24.9, 7.0 Hz, 3H),0.86 (dd, J=22.6, 6.9 Hz, 3H); ESI-MS m/z 463.29 (M+1)⁺.

(7S)-7-Isopropyl-4,8-dimethyl-2-(((R)-1-(3,4,5-trifluorobenzoyl)pyrrolidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

This compound was prepared via the same general 3 step procedurerecorded for Table H examples to provide the title compound. ¹H NMR (400MHz, Methanol-d4) δ 7.36 (dt, J=14.9, 7.4 Hz, 2H), 4.62-4.51 (m, 0.5H),4.48-4.40 (m, 0.5H), 4.00-3.75 (m, 2.5H), 3.71-3.50 (m, 2H), 3.43 (dd,J=10.8, 5.0 Hz, 0.5H), 3.18 (s, 1.5H), 3.07 (s, 1.5H), 2.38-2.12 (m,5H), 2.11-1.95 (m, 1H), 1.03 (dd, J=10.3, 7.0 Hz, 3H), 0.86 (dd, J=11.6,6.9 Hz, 3H); ESI-MS m/z 463.24 (M+1)⁺.

Example 2AA General Scheme and Procedure for Examples in Table 25General Procedure for Examples in Table 25

Sodium triacetoxyborohydride (184 mg, 0.87 mmol) was added to a solutionof(7S)-2-(azetidin-3-ylamino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onetrifluoroacetic acid (300 mg, 0.579 mmol), 3,4,5-trifluorobenzaldehyde(102 mg, 0.64 mmol), and acetic acid (65 μL, 1.157 mmol) indichloromethane (3 ml) and stirred at room temperature for 12 hours. Thereaction was quenched with saturated sodium bicarbonate (3 ml). Theorganic layer was separated and the aqueous extracted with 10 ml ofdichloromethane. The combined organic layers were dried and evaporatedto afford the crude product. The product was purified by reverse phasechromatography (C18, 100 g column) eluting with 5-90% acetonitrile/water(0.1% TFA). The desired fractions were evaporated and neutralized toafford the desired product.

The following examples of Table 25 were prepared by the generalprocedure described above.

TABLE 25 Comp. No. Ring B M + 1 591

435.29 603

429.3 649

450.2 650

449.25

Compound 591.(S)-7-isopropyl-4,8-dimethyl-2-((1-(3,4,5-trifluorobenzyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.15-7.04 (m, 2H), 4.58 (p, J=7.0 Hz,1H), 3.91 (d, J=4.4 Hz, 1H), 3.76 (dd, J=11.6, 5.4 Hz, 2H), 3.67 (s,2H), 3.14-3.03 (m, 5H), 2.28-2.16 (m, 1H), 2.15 (s, 3H), 1.02 (d, J=7.0Hz, 3H), 0.85 (d, J=6.9 Hz, 3H).

Compound 603.(S)-2-((1-(4-fluoro-2-methoxybenzyl)azetidin-3-yl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.21 (t, J=7.5 Hz, 1H), 6.81-6.71 (m,1H), 6.63 (td, J=8.3, 2.3 Hz, 1H), 4.53 (p, J=7.0 Hz, 1H), 3.89 (d,J=4.3 Hz, 1H), 3.83 (s, 3H), 3.71 (d, J=2.8 Hz, 2H), 3.65 (s, 2H),3.13-3.02 (m, 5H), 2.20 (dt, J=6.9, 5.6 Hz, 1H), 2.14 (s, 3H), 1.02 (d,J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H)

Compound 649.(S)-7-isopropyl-4,8-dimethyl-2-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.65 (s, 1H), 7.98 (d, J=8.0 Hz, 1H),7.79 (d, J=8.1 Hz, 1H), 4.59 (p, J=7.0 Hz, 1H), 3.90 (d, J=4.4 Hz, 1H),3.81 (s, 2H), 3.76 (ddd, J=9.8, 5.1, 2.5 Hz, 2H), 3.14-3.05 (m, 5H),2.25-2.16 (m, 1H), 2.15 (s, 4H), 1.02 (d, J=7.0 Hz, 3H), 0.85 (d, J=6.9Hz, 3H)

Compound 650.(S)-7-isopropyl-4,8-dimethyl-2-((1-(4-(trifluoromethyl)benzyl)azetidin-3-yl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.62 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.1Hz, 2H), 4.59 (p, J=7.0 Hz, 1H), 3.90 (d, J=4.4 Hz, 1H), 3.82-3.69 (m,4H), 3.17-2.98 (m, 5H), 2.29-2.09 (m, 5H), 1.02 (d, J=7.0 Hz, 3H), 0.85(d, J=6.9 Hz, 3H).

Example 2BB General Scheme and Procedure for Examples in Table 26General Procedure for Examples in Table 26

Step 1:(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

A mixture of(S)-2-chloro-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one (5g, 19.5 mmol), cis-(3-aminocyclobutyl)methanol hydrochloride (2.95 g,21.4 mmol), and sodium tert-butoxide (8.07 g, 84 mmol) were taken intot-butanol (80 ml) and dioxane (75 ml) and stirred for 20 mins until mostof the solids were dissolved. The mixture was purged with nitrogen for15 minutes. tBuXPhos palladacycle (Gen 1) (260 mg, 0.4 mmol) was addedto the mixture then purged with nitrogen for 10 minutes. The reactionwas stirred at 60° C. for 1 hour. The reaction mixture was evaporated invacuo and the resulting residue was taken into 100 ml of water andextracted with dichloromethane (2×80 ml). The extracts were combined,washed with brine, dried over anhydrous sodium sulfate, filtered, andevaporated in vacuo to afford the crude product. The product waspurified by column chromatography (120 g SiO₂ column) eluting with agradient of dichloromethane to 20% methanol. The desired fractions werecombined and evaporated to afford a light green solid, 3.5 g. The solidwas dissolved in dichloromethane (30 ml), added MP-TMP resin (1.5 g) andstirred for 12 hours. This was filtered through Celite and the filtrateevaporated in vacuo. The resulting solid was washed with heptanes andfiltered to afford 3.4 g (55% yield) of the product as a white solid. 1HNMR (300 MHz, CDCl₃) δ 5.55 (s, 1H), 4.32 (dd, J=15.7, 8.1 Hz, 1H),3.97-3.85 (m, 1H), 3.63 (d, J=5.9 Hz, 2H), 3.15 (s, 3H), 2.62-2.44 (m,2H), 2.31-2.15 (m, 4H), 1.81-1.62 (m, 2H), 1.08 (d, J=6.9 Hz, 3H), 0.93(d, J=6.9 Hz, 3H). ESI-MS m/z 320.09 (M+1)⁺; [α]^(D)=+258.98 (c=1.0,CHCl3) at 22.3° C.

Step 2: General Procedure

A mixture of(7S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(1 equiv), triphenyl phosphine (2.1 equiv), and the heterocycle (hydroxyheterocycle, pyrazole, or imidazole derivative; 1.6 equiv) was takeninto THF (25 vol equiv). Diethylazodicarboxylate (2.1 equiv) was addedto the mixture dropwise at room temperature then heated to 50° C. for 2hours. The crude products were purified by preparative reverse phaseHPLC (C18 column) eluting with 10-95% acetonitrile/water (0.5 mMHCl) toprovide the products described in Table 26.

TABLE 26 Comp. No. L₂-Ring B [α]_(D) M + 1 551

+37.8 c = 1.0 DMSO 465.27 570

431.28 571

411.25 572

422.23 573

427.24 574

415.28 575

468.21 580

440.33 581

478.26 582

452.22 583

404.23 584

453.3 585

453.3 598

481.23 679

438.31 680

438.31 690

438.56 693

400.23 694

440.24 695

430.15 696

439.26

Compound 551.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H1)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.40 (d, J=2.7 Hz, 1H), 7.78 (t, J=7.4Hz, 1H), 7.69-7.63 (m, 1H), 4.53-4.33 (m, 1H), 4.17 (dd, J=4.2, 2.2 Hz,3H), 3.35-3.30 (m, 1H), 3.29 (d, J=6.3 Hz, 3H), 2.71-2.56 (m, 3H), 2.34(d, J=8.5 Hz, 3H), 2.14-1.98 (m, 2H), 1.11 (d, J=6.9 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H)

Compound 570.(S)-2-((cis-3-(((6-chloropyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

1H NMR (400 MHz, Methanol-d₄) δ 8.09 (d, J=3.0 Hz, 1H), 7.50 (dd, J=8.8,3.1 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.50-4.32 (m, 1H), 4.08 (d, J=5.0Hz, 2H), 3.28 (s, 3H), 2.71-2.53 (m, 3H), 2.36 (dd, J=7.0, 3.1 Hz, OH),2.32 (s, 3H), 2.08-1.94 (m, 2H), 1.11 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9Hz, 3H).

Compound 571.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(((6-methylpyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.46 (d, J=2.8 Hz, 1H), 8.16 (dd, J=9.0,2.8 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 4.46 (p, J=8.1 Hz, 1H), 4.22 (d,J=4.7 Hz, 2H), 4.15 (d, J=3.8 Hz, 1H), 3.28 (s, 3H), 2.72 (s, 3H), 2.64(tt, J=6.2, 1.4 Hz, 2H), 2.40-2.32 (m, 1H), 2.31 (s, 3H), 2.14-1.92 (m,2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 572.5-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)methoxy)picolinonitrile

¹H NMR (400 MHz, Methanol-d₄) δ 8.39 (dd, J=2.9, 0.6 Hz, 1H), 7.82 (dd,J=8.7, 0.6 Hz, 1H), 7.53 (dd, J=8.7, 2.9 Hz, 1H), 4.48-4.35 (m, 1H),4.15 (t, J=4.7 Hz, 3H), 3.28 (s, 3H), 2.65-2.57 (m, 3H), 2.35 (dd,J=7.0, 3.9 Hz, OH), 2.31 (s, 3H), 2.11-1.94 (m, 2H), 1.11 (d, J=7.0 Hz,3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 573.(S)-7-isopropyl-2-((cis-3-(((6-methoxypyridin-3-yl)oxy)methyl)cyclobutyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.95 (dd, J=3.2, 0.6 Hz, 1H), 7.87 (dd,J=9.3, 3.1 Hz, 1H), 7.23 (dd, J=9.3, 0.6 Hz, 1H), 4.52-4.36 (m, 1H),4.15 (d, J=3.8 Hz, 1H), 4.05 (s, 3H), 3.28 (s, 3H), 2.69-2.56 (m, 2H),2.35 (dt, J=7.0, 3.5 Hz, 1H), 2.31 (s, 3H), 2.03 (dtd, J=10.3, 8.9, 7.2Hz, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 574.(S)-2-((cis-3-(((6-fluoropyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.88-7.74 (m, 1H), 7.55 (ddd, J=9.0,6.4, 3.2 Hz, 1H), 7.00 (ddd, J=8.9, 3.1, 0.5 Hz, 1H), 4.39 (d, J=7.6 Hz,1H), 4.15 (d, J=3.8 Hz, 1H), 4.04 (d, J=5.3 Hz, 2H), 3.28 (s, 3H),2.67-2.57 (m, 2H), 2.39-2.33 (m, OH), 2.30 (s, 3H), 2.08-1.95 (m, 2H),1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 575.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.39 (d, J=0.9 Hz, 1H), 4.39-4.28 (m,1H), 4.14 (d, J=3.8 Hz, 1H), 4.00 (d, J=5.5 Hz, 2H), 3.89 (q, J=0.9 Hz,3H), 3.27 (s, 3H), 2.61-2.49 (m, 2H), 2.40-2.33 (m, 1H), 2.30 (s, 3H),1.96 (dtd, J=10.7, 3.8, 1.7 Hz, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H)

Compound 580.(S)-2-((cis-3-((benzo[d][1,3]dioxol-5-yloxy)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 8.62 (s, 1H), 6.67-6.54 (m, 1H),6.46-6.37 (m, 1H), 6.24 (dd, J=8.5, 2.5 Hz, 1H), 5.83 (s, 2H), 4.77 (d,J=7.8 Hz, 1H), 4.36-4.22 (m, 1H), 3.78 (dd, J=6.2, 5.1 Hz, 3H), 3.03 (s,3H), 2.59-2.42 (m, 2H), 2.44-2.29 (m, 1H), 2.22-2.13 (m, 1H), 2.12 (s,3H), 1.72-1.59 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.84 (d, J=6.9 Hz, 3H).

Compound 581.(S)-2-((cis-3-((3-cyclopropyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 6.30 (2s, 1H), 4.39-4.24 (m, 3H), 4.19(dd, J=6.8, 4.4 Hz, 2H), 3.26 (s, 3H), 2.59-2.48 (m, 1H), 2.34 (dt,J=7.0, 3.5 Hz, 1H), 2.29 (s, 3H), 1.98-1.83 (m, 2H), 1.29 (q, J=7.0 Hz,3H), 1.10 (d, J=6.9 Hz, 3H), 0.97-0.91 (m, 1H), 0.88 (d, J=6.9 Hz, 3H),0.80-0.63 (m, 2H).

Compound 582.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 6.57, 6.31 (2s, 1H), 4.34-4.28 (m, 1H),4.21 (dd, J=10.1, 6.4 Hz, 2H), 4.13 (d, J=3.8 Hz, 1H), 3.25 (s, 3H),2.59-2.48 (2s, 3H), 2.31-2.23 (m, 4H), 1.96-1.80 (m, 2H), 1.10 (d, J=7.0Hz, 3H), 0.88 (d, J=7.0 Hz, 3H).

Compound 583.(S)-2-((cis-3-((3-chloro-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=2.4 Hz, 1H), 6.27 (d, J=2.4Hz, 1H), 4.31 (q, J=7.9 Hz, 1H), 4.24 (d, J=6.3 Hz, 1H), 4.18-4.10 (m,2H), 3.27-3.17 (m, 3H), 2.59-2.47 (m, 2H), 2.38-2.32 (m, 1H), 2.29 (d,J=2.6 Hz, 3H), 1.93-1.79 (m, 1H), 1.10 (dd, J=7.0, 2.2 Hz, 3H),0.92-0.80 (m, 3H).

Compound 584.(S)-2-((cis-3-((3-amino-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 6.84 (s, 1H), 4.39 (d, J=8.0 Hz, OH),4.35 (s, 1H), 4.14 (d, J=3.7 Hz, 1H), 3.27 (d, J=3.8 Hz, 3H), 2.69-2.50(m, 3H), 2.41-2.32 (m, 1H), 2.31 (s, 3H), 2.04-1.91 (m, 2H), 1.26 (t,J=7.1 Hz, 1H), 1.10 (d, J=6.9 Hz, 3H), 0.88 (dd, J=6.9, 2.0 Hz, 3H).

Compound 585.(S)-2-((cis-3-((5-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 4.30 (dt, J=15.7, 8.2 Hz, 1H), 4.18-4.10(m, 1H), 4.04 (d, J=6.0 Hz, 1H), 3.26 (d, J=5.6 Hz, 3H), 2.64-2.43 (m,1H), 2.34 (dq, J=10.2, 3.5 Hz, OH), 2.28 (s, 2H), 1.95-1.78 (m, 2H),1.10 (dd, J=7.1, 1.9 Hz, 3H), 0.88 (dd, J=7.1, 2.1 Hz, 3H).

Compound 598.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(((6-(trifluoromethoxy)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.08-7.85 (m, 1H), 7.54 (dd, J=8.9, 3.1Hz, 1H), 7.13 (d, J=8.9 Hz, 1H), 4.50-4.30 (m, 1H), 4.15 (d, J=3.9 Hz,1H), 4.07 (d, J=5.3 Hz, 2H), 3.28 (s, 3H), 2.73-2.52 (m, 2H), 2.36 (td,J=7.0, 3.9 Hz, 1H), 2.30 (s, 3H), 2.02 (ddd, J=9.8, 5.8, 3.5 Hz, 2H),1.11 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 679.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-imidazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 9.42 (s, 1H), 8.37 (s, 1H), 4.48 (d,J=6.0 Hz, 3H), 4.15 (d, J=3.5 Hz, 1H), 3.27 (s, 3H), 2.67 (d, J=13.6 Hz,3H), 2.31 (s, 4H), 2.03 (dt, J=13.9, 8.1 Hz, 2H), 1.11 (d, J=6.8 Hz,3H), 0.89 (d, J=6.7 Hz, 3H).

Compound 680.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 9.31 (d, J=1.4 Hz, 1H), 8.42 (t, J=1.4Hz, 1H), 4.44 (d, J=7.0 Hz, 2H), 4.16 (d, J=3.7 Hz, 1H), 3.28 (d, J=1.7Hz, 3H), 2.65 (dddd, J=20.3, 18.3, 10.0, 4.2 Hz, 2H), 2.32 (d, J=1.7 Hz,3H), 2.08-1.93 (m, 1H), 1.38-1.21 (m, 3H), 1.10 (d, J=6.9 Hz, 3H), 0.89(dd, J=6.9, 1.6 Hz, 3H).

Compound 690.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (dd, J=2.0, 0.8 Hz, 1H), 6.74 (d,J=2.0 Hz, 1H), 4.31 (d, J=6.7 Hz, 3H), 4.14 (d, J=3.8 Hz, 1H), 3.32 (s,3H), 3.25 (s, 3H), 2.61-2.50 (m, 2H), 2.34 (dd, J=7.0, 3.8 Hz, OH), 2.29(s, 3H), 1.92 (dtd, J=11.4, 9.0, 6.3 Hz, 2H), 1.10 (d, J=6.9 Hz, 3H),0.88 (d, J=6.9 Hz, 3H).

Compound 693.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(((1-methyl-1H-pyrazol-5-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.57 (t, J=2.4 Hz, 1H), 5.86 (dq, J=2.6,1.5 Hz, 1H), 4.40 (t, J=7.7 Hz, 1H), 4.17-4.14 (m, 2H), 4.13 (s, 1H),3.80 (d, J=1.1 Hz, 3H), 3.28 (s, 3H), 2.65-2.50 (m, 3H), 2.35 (ddd,J=14.6, 7.3, 4.2 Hz, 1H), 2.31 (s, 3H), 2.07-1.85 (m, 2H), 1.11 (d,J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 694.3-fluoro-5-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)methoxy)picolinonitrile

¹H NMR (400 MHz, Methanol-d₄) δ 8.27 (dd, J=2.4, 1.0 Hz, 1H), 7.49 (dd,J=11.0, 2.4 Hz, 1H), 4.39 (d, J=9.7 Hz, 1H), 4.16 (dd, J=6.3, 4.3 Hz,3H), 3.29 (s, 3H), 2.69-2.55 (m, 4H), 2.34 (td, J=7.0, 3.9 Hz, 1H), 2.29(s, 3H), 2.02 (q, J=7.5, 6.2 Hz, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H).

Compound 695.5-chloro-2-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)methyl)-2H-1,2,3-triazole-4-carbonitrile

1H NMR (400 MHz, Methanol-d4) δ 4.59 (d, J=6.9 Hz, 2H), 4.37 (q, J=8.2Hz, 1H), 4.14 (d, J=3.8 Hz, 1H), 3.26 (s, 3H), 2.78-2.67 (m, 1H), 2.59(dddd, J=11.5, 6.1, 4.8, 2.1 Hz, 2H), 2.39-2.33 (m, OH), 2.30 (s, 3H),1.95 (dtd, J=11.8, 9.2, 6.3 Hz, 2H), 1.10 (d, J=6.9 Hz, 3H), 0.88 (d,J=6.9 Hz, 3H).

Compound 696.(S)-2-((cis-3-(((6-acetylpyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.47 (d, J=2.8 Hz, 1H), 8.24 (dd, J=9.1,2.8 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 4.53-4.43 (m, 1H), 4.28 (d, J=4.6Hz, 1H), 4.16 (dd, J=11.6, 4.3 Hz, 2H), 3.28 (s, 3H), 2.64 (q, J=5.5,4.2 Hz, 4H), 2.35 (dd, J=7.0, 3.9 Hz, OH), 2.31 (s, 3H), 2.06 (ddt,J=14.7, 8.2, 3.5 Hz, 2H), 1.67 (s, 2H), 1.11 (d, J=6.9 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H).

Example 2CC General Scheme and Procedure for Examples in Table 27

General Procedure for Examples in Table 27 Compound 646

A mixture of(7S)-2-chloro-7-ethyl-4,8-dimethyl-5,7-dihydropteridin-6-one (81 mg,0.34 mmol), 3-[[6-(trifluoromethyl)-3-pyridyl]oxymethyl]cyclobutanaminehydrochloride (79 mg, 0.28 mmol) and TFA (40 μL, 0.56 mmol) in n-BuOH (1mL) was heated at 150° C. for 90 minutes using the microwave reactor.The reaction was evaporated in vacuo and the crude product purified byreverse phase chromatography eluting with a gradient of 5-90%acetonitrile/water (5 mM HCl). Evaporation of the desired fractionsafforded the product as the HCl salt (56 mg, 41% yield). ¹H NMR (400MHz, Methanol-d₄) δ 8.37 (d, J=2.8 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.55(dd, J=8.8, 2.8 Hz, 1H), 4.49-4.36 (m, 1H), 4.32 (dd, J=5.8, 3.4 Hz,1H), 4.15 (d, J=4.8 Hz, 2H), 3.25 (s, 3H), 2.71-2.52 (m, 3H), 2.31 (s,3H), 2.10-1.90 (m, 4H), 0.86 (t, J=7.4 Hz, 3H). ESI-MS m/z 451.22(M+1)⁺.

Examples prepared by general procedure described above via reaction ofIntermediate A-# and B-195 are provided in Table 27.

TABLE 27 Compound No. R₃ Int. A [α]_(D) M + 1 646 -Et A-8 26.9 C = 1.0DMSO 451.22 643 (R)- CH(OCH3)CH3 A-59 98.8 C = 1.0 MeOH 481.25 671

A-66 117.6 c = 0.5 MeOH 493.27 551 (CH₃)₂CH- B-213 39.7 c = 1.04 MeOH465.47

Compound 646.(S)-7-ethyl-4,8-dimethyl-2-((cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.37 (d, J=2.8 Hz, 1H), 7.74 (d, J=8.7Hz, 1H), 7.55 (dd, J=8.8, 2.8 Hz, 1H), 4.49-4.36 (m, 1H), 4.32 (dd,J=5.8, 3.4 Hz, 1H), 4.15 (d, J=4.8 Hz, 2H), 3.25 (s, 3H), 2.71-2.52 (m,3H), 2.31 (s, 3H), 2.10-1.90 (m, 4H), 0.86 (t, J=7.4 Hz, 3H).

Compound 643.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 9.49 (s, 1H), 8.35 (d, J=2.8 Hz, 1H),7.58 (d, J=8.7 Hz, 1H), 7.25 (dd, J=8.6, 2.8 Hz, 1H), 5.00 (d, J=7.6 Hz,1H), 4.49-4.30 (m, 1H), 4.01 (d, J=5.7 Hz, 2H), 3.90 (d, J=6.2 Hz, 1H),3.53 (p, J=6.3 Hz, 1H), 3.27 (s, 3H), 3.16 (s, 3H), 2.61 (ddd, J=11.7,9.1, 6.8 Hz, 2H), 2.49 (tdd, J=9.2, 6.9, 4.5 Hz, 1H), 2.22 (s, 3H), 1.77(qd, J=9.1, 4.1 Hz, 2H), 1.20 (d, J=6.4 Hz, 3H).

Compound 671.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.44 (d, J=2.8 Hz, 1H), 7.83(d, J=8.7 Hz, 1H), 7.59 (dd, J=8.5, 2.7 Hz, 1H), 6.51 (s, 1H), 4.31-4.17(m, 2H), 4.11 (d, J=5.5 Hz, 2H), 3.10 (s, 3H), 3.06 (s, 3H), 2.40 (t,J=6.0 Hz, 3H), 2.29-2.19 (m, 1H), 2.17-2.05 (m, 5H), 1.98 (dd, J=18.9,9.0 Hz, 1H), 1.86-1.63 (m, 3H), 1.63-1.50 (m, 1H).

Compound 750.(1s,3s)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)cyclobutan-1-amine

¹H NMR (300 MHz, Methanol-d4) δ 8.61 (s, 2H), 4.20 (d, J=5.5 Hz, 2H),3.73 (tt, J=8.7, 7.6 Hz, 1H), 2.77-2.60 (m, 1H), 2.57-2.40 (m, 2H),2.24-1.94 (m, 2H); ESI-MS m/z calc. 247.09, found 248.17 (M+1)⁺;Retention time: 0.58 minutes

Example 2DD General Scheme and Procedure for Examples in Table 28

General Procedure for Examples in Table 28

The examples in Table 28 were prepared by the same procedure describedfor Table 27 via reaction of an intermediate A-# and Intermediate B-211

TABLE 28 Compound No. R₃ [α]_(D) M + 1 714 —CH3 11.1 c = 1.0 437.21 DMSO713 —Et 24.2 c = 1.0 451.22 DMSO 712 (R)—CH(OCH3)CH₃ 33.8 c = 1.0 481.21DMSO 711 -iPr 36.6 c = 1.0 465.22 DMSO

Compound 714.(S)-4,7,8-trimethyl-2-((cis-3-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.25 (d, J=1.3 Hz, 1H), 8.22 (d, J=1.1Hz, 1H), 4.30 (q, J=6.9 Hz, 1H), 3.54 (d, J=6.8 Hz, 2H), 3.24 (s, 3H),2.69-2.57 (m, 2H), 2.32 (s, 3H), 1.91 (qt, J=9.3, 2.1 Hz, 2H), 1.52 (d,J=7.0 Hz, 3H).

Compound 713.(S)-7-ethyl-4,8-dimethyl-2-((cis-3-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.23 (s, 1H), 8.18 (d, J=1.3 Hz, 1H),4.39-4.26 (m, 2H), 3.52 (d, J=6.8 Hz, 2H), 3.23 (s, 3H), 2.68-2.53 (m,2H), 2.44 (tt, J=9.4, 7.1 Hz, 1H), 2.30 (s, 3H), 2.11-1.99 (m, 2H), 1.89(ddt, J=11.2, 6.8, 4.6 Hz, 2H), 0.86 (t, J=7.5 Hz, 3H).

Compound 712.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((cis-3-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.26 (d, J=1.2 Hz, 1H), 8.23 (s, 1H),4.39 (t, J=8.1 Hz, 1H), 4.22 (d, J=3.9 Hz, 1H), 3.78 (tt, J=6.4, 3.2 Hz,1H), 3.54 (d, J=6.8 Hz, 2H), 3.33 (s, 3H), 3.29 (s, 3H), 2.72-2.58 (m,2H), 2.31 (s, 3H), 1.92 (dq, J=11.4, 8.8 Hz, 2H), 1.28 (d, J=6.5 Hz, 3H)

Compound 711.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(((5-(trifluoromethyl)pyrazin-2-yl)amino)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.23 (t, J=1.0 Hz, 1H), 8.17 (d, J=1.3Hz, 1H), 4.37 (q, J=8.2 Hz, 1H), 4.14 (d, J=3.8 Hz, 1H), 3.52 (d, J=6.7Hz, 2H), 3.27 (s, 3H), 2.69-2.57 (m, 2H), 2.52-2.44 (m, 1H), 2.34 (dt,J=7.0, 3.5 Hz, 1H), 2.30 (s, 3H), 1.89 (dtd, J=11.7, 9.3, 6.0 Hz, 2H),1.10 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H).

Example 2EE General Scheme and Procedure for Examples in Table 29General Procedure for Examples in Table 29

(S)-2-((cis-3-(hydroxymethyl)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

A mixture of(S)-2-chloro-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(1.17 g, 4.55 mmol),cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutan-1-aminehydrochloride (1.16 g, 21.4 mmol), and a 2M solution of sodiumtert-butoxide (8.07 g, 84 mmol) in THF were taken into t-butanol (35 ml)and stirred for 20 mins until most of the solids were dissolved. Themixture was purged with nitrogen for 15 minutes. tBuXPhos palladacycle(Gen 1) (150 mg, 0.22 mmol) was added to the mixture, then purged withnitrogen for 10 minutes. The reaction was stirred at 60° C. for 1 hour.The reaction mixture was evaporated in vacuo and the resulting residuewas taken into 100 ml of water and extracted with dichloromethane (2×80ml). The extracts were combined, washed with brine, dried over anhydroussodium sulfate, filtered, and evaporated in vacuo to afford the crudeproduct. The product was purified by column chromatography (120 g SiO₂column) eluting with a gradient of dichloromethane to 20% methanol. Thedesired fractions were combined and evaporated, 3.5 g. The resultingmaterial was dissolved in dichloromethane (30 ml), added MP-TMP resin(1.5 g) and stirred for 12 hours. This was filtered through Celite andthe filtrate evaporated in vacuo. The resulting material was washed withheptanes and filtered to afford 3.4 g (55% yield) of the product.

Table 29 provides examples prepared by general procedure described abovevia reaction of Intermediate A-# and B-139.

TABLE 29 Comp. No. R₃ Int A [α]_(D) M + 1 512 -iPr A-9 102.0 438.35 c =1, MeOH 593 -CH₂CH₃ A-8 60.9 424.3 c = 1.0 DMSO 588 -(R)CH(OCH₃) A-59101.98 454.33 CH₃ c = 1, MeOH 676

A-68 69.36 c = 0.5, CHCl₃ 466.29 723 -CH₂OtBu A-63 42.2 482.46 c = 0.5CHCl3 743 -CH2OH ** 13.8 426.4 c = 0.5 MeOH ** Compound was prepared bydeprotection of the t-butyl ether of Compound 723

Compound 512.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.40 (d, J=1.2 Hz, 1H), 6.51 (d,J=2.0 Hz, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.41-4.27 (m, 1H), 4.21 (d, J=6.0Hz, 2H), 3.87 (d, J=4.3 Hz, 1H), 3.10 (s, 3H), 2.67-2.43 (m, 3H),2.28-2.22 (m, 1H), 2.21 (d, J=5.7 Hz, 3H), 1.79-1.55 (m, 2H), 1.07 (d,J=6.9 Hz, 3H), 0.92 (d, J=6.9 Hz, 3H).

Compound 593.(S)-7-ethyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H), 7.39 (d, J=2.3 Hz, 1H),6.50 (d, J=2.3 Hz, 1H), 5.03 (d, J=7.5 Hz, 1H), 4.30 (q, J=7.6 Hz, 1H),4.19 (d, J=5.9 Hz, 2H), 4.04 (dd, J=6.5, 3.7 Hz, 1H), 3.04 (s, 3H), 2.55(p, J=7.8 Hz, 3H), 2.21 (s, 3H), 1.95 (ddp, J=11.1, 7.4, 3.7 Hz, 1H),1.83 (dt, J=14.2, 7.1 Hz, 1H), 1.65 (tdd, J=11.8, 9.0, 5.1 Hz, 2H), 0.89(t, J=7.5 Hz, 3H).

Compound 588.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.39 (dt, J=2.2, 0.9 Hz,1H), 6.50 (d, J=2.2 Hz, 1H), 5.14 (d, J=8.1 Hz, 1H), 4.31 (dq, J=11.0,7.7, 7.1 Hz, 1H), 4.20 (s, 1H), 4.12 (qd, J=7.1, 0.9 Hz, 1H), 3.92 (dd,J=6.1, 1.0 Hz, 1H), 3.63-3.51 (m, 1H), 3.28 (d, J=1.0 Hz, 3H), 3.17 (d,J=0.9 Hz, 3H), 2.66-2.46 (m, 3H), 2.22 (s, 3H), 1.75-1.59 (m, 2H), 1.27(dd, J=7.2, 1.0 Hz, 1H), 1.25-1.11 (m, 3H).

Compound 676.7-(1-methoxycyclopropyl)-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 7.41 (s, 1H), 6.52 (d, J=1.9 Hz, 1H),4.93 (s, 1H), 4.43-4.28 (m, 1H), 4.22 (d, J=5.5 Hz, 2H), 3.79-3.59 (m,1H), 3.23-3.18 (m, 3H), 3.17 (d, J=1.7 Hz, 3H), 2.68-2.44 (m, 3H), 2.22(d, J=3.7 Hz, 3H), 1.77-1.55 (m, 3H), 1.41-1.10 (m, 4H), 0.84-0.64 (m,1H).

Compound 723.(S)-7-(tert-butoxymethyl)-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.40 (d, J=2.4 Hz, 1H),6.52 (d, J=2.4 Hz, 1H), 4.83 (s, 1H), 4.30 (d, J=13.7 Hz, 1H), 4.21 (d,J=5.6 Hz, 2H), 4.08 (t, J=3.3 Hz, 1H), 3.70 (d, J=3.2 Hz, 2H), 3.08 (s,4H), 2.58 (t, J=6.5 Hz, 3H), 2.17 (d, J=2.0 Hz, 3H), 1.05 (s, 10H).

Compound 743.(S)-7-(hydroxymethyl)-4,8-dimethyl-2-(((1s,3R)-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 7.76 (s, 1H), 6.58 (d, J=2.3 Hz, 1H),4.35 (d, J=7.8 Hz, 1H), 4.32-4.17 (m, 2H), 4.11-3.85 (m, 2H), 3.81-3.51(m, 3H), 3.25 (s, 3H), 2.71-2.40 (m, 3H), 2.29 (s, 3H), 1.89 (q, J=10.8,9.1 Hz, 2H).

Example 2FF General Scheme and Procedure for Examples in Table 30

General Procedure for Examples in Table 30

The examples in Table 30 were prepared by the same procedure that wasreported for Table 29 via reaction of Intermediate A-# and B-210.

TABLE 30 Comp. No. R₃ Int A [α]_(D) M + 1 690 iPr A-9 42.3 c = 1.0438.56 DMSO 691 (R)—CH(OCH₃)CH₃ A-59 454.55 692 —Et A-8 15.6 c = 1.0424.21 DMSO 698 —CH₃ A-2 7.3 c = 1.0 410.26 DMSO

Compound 690.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (dd, J=2.0, 0.8 Hz, 1H), 6.74 (d,J=2.0 Hz, 1H), 4.31 (d, J=6.7 Hz, 3H), 4.14 (d, J=3.8 Hz, 1H), 3.32 (s,3H), 3.25 (s, 3H), 2.61-2.50 (m, 2H), 2.34 (dd, J=7.0, 3.8 Hz, OH), 2.29(s, 3H), 1.92 (dtd, J=11.4, 9.0, 6.3 Hz, 2H), 1.10 (d, J=6.9 Hz, 3H),0.88 (d, J=6.9 Hz, 3H).

Compound 691.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((cis-3-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (dd, J=2.0, 0.8 Hz, 1H), 6.74 (dd,J=2.0, 0.8 Hz, 1H), 4.37 (d, J=3.7 Hz, 1H), 4.32 (d, J=6.6 Hz, 3H), 4.21(d, J=3.9 Hz, 1H), 3.88-3.73 (m, 2H), 3.31 (s, 3H), 3.27 (s, 2H),2.62-2.47 (m, 2H), 2.30 (s, 3H), 1.33-1.28 (m, 3H)

Compound 692.(S)-7-ethyl-4,8-dimethyl-2-((cis-3-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ7.90-7.49 (m, 1H), 6.66 (dd, J=62.4, 2.2Hz, 1H), 4.40-4.18 (m, 4H), 3.22 (s, 3H), 2.73-2.46 (m, 3H), 2.30 (s,3H), 2.15-1.84 (m, 4H), 0.85 (t, J=7.5 Hz, 3H)

Compound 698.(S)-4,7,8-trimethyl-2-((cis-3-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ7.82-7.50 (m, 1H), 6.65 (dd, J=61.9, 2.2Hz, 1H), 4.37-4.23 (m, 4H), 3.22 (s, 3H), 2.69-2.44 (m, 3H), 2.29 (s,3H), 1.90 (dddd, J=18.0, 11.4, 5.2, 2.0 Hz, 2H), 1.51 (d, J=7.0 Hz, 3H).

Example 2GG General Scheme and Procedure for Examples in Table 31General Procedure for Examples in Table 31

The examples in Table 31 were prepared by the same procedure that wasreported for Table 28 via reaction of Intermediate A-# and B-197b.

TABLE 31 Comp. No. R₃ Int A [α]_(D) M + 1 730 -iPr A-9 424.28 731—(R)—CH(OCH3)CH3 A-59 440.34

Compound 730.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (s, 1H), 6.82 (s, 1H), 5.17 (td,J=8.7, 4.5 Hz, 1H), 4.79-4.67 (m, OH), 4.15 (d, J=3.8 Hz, 1H), 3.27 (s,3H), 3.04 (dtt, J=11.0, 5.7, 2.8 Hz, 2H), 2.83-2.69 (m, 2H), 2.42-2.34(m, OH), 2.32 (s, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 731.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((trans-3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.71-7.62 (m, 1H), 6.80-6.70 (m, 1H),5.19 (tt, J=9.3, 5.6 Hz, 1H), 4.80-4.72 (m, OH), 4.23 (d, J=3.9 Hz, 1H),3.79 (dt, J=6.6, 3.3 Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 3.05 (ddt,J=8.4, 5.3, 3.2 Hz, 1H), 2.83-2.71 (m, 2H), 2.34 (s, 3H), 1.29 (d, J=6.5Hz, 3H).

Example 2HH General Scheme and Procedure for Examples in Table 32

Step 1. tert-Butyl(cis-3-(((7S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamate

A THF solution of sodium tert-butoxide (2 M solution; 17 ml, 33.4 mmol)was added to a mixture of(7S)-2-chloro-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one (2.446g, 9.507 mmol), tert-butyl (trans-3-aminocyclobutyl)carbamate (1.773 g,9.517 mmol) and tBuXPhoS (Gen 1; 261.4 mg, 0.3806 mmol) in 40 ml oftert-butanol under a nitrogen. The reaction was stirred for 30 mins. at50 C. The reaction was quenched with ice cooled ammonium chloride (200ml) and extracted with ethyl acetate (3×100 ml). The extracts werecombined, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was stirred with TMT scavenger resin to remove Pd, filtered,and evaporated in vacuo. The crude product was purified by columnchromatography (SiO2) eluting with a gradient of dichloromethane to 10%methanol. The relevant fractions were combined and evaporated in vacuoto afford the title product (2.5 g, 64.9% yield). 1H NMR (400 MHz,CDCl₃) δ 7.96 (s, 1H), 4.77 (d, J=7.1 Hz, 1H), 4.69 (d, J=7.6 Hz, 1H),4.23-3.96 (m, 2H), 3.89 (d, J=4.2 Hz, 2H), 3.12 (s, 3H), 2.86 (d, J=5.5Hz, 2H), 2.29-2.21 (m, 1H), 2.19 (s, 3H), 2.07 (s, 1H), 1.83-1.60 (m,3H), 1.46 (s, 9H), 1.28 (dd, J=7.5, 6.7 Hz, 1H), 1.08 (d, J=6.9 Hz, 3H),0.93 (t, J=7.1 Hz, 3H). ESI-MS m/z 405.35 (M+1).

Step 2.(7S)-2-((cis-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride

^(tert)-Butyl(trans-3-(((7S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamate(2.17 g, 5.36 mmol) was dissolved in methanol (30 ml). A 4 M solution ofhydrogen chloride (11 ml, 44 mmol) in dioxane was added to the solutionand the mixture heated to 50 C for 30 minutes. The reaction wasevaporated in vacuo and the resulting solid was washed with heptanes,filtered, and dried under vacuum at 50 C to afford the title product asa white solid, 2.31 g (quantitative yield). 1H NMR (400 MHz,Methanol-d4) δ 4.43-4.26 (m, 1H), 4.15 (d, J=3.8 Hz, 1H), 3.58 (ddd,J=22.7, 16.2, 7.5 Hz, 1H), 3.28 (s, 3H), 2.98-2.81 (m, 2H), 2.38-2.31(m, 1H), 2.30 (d, J=3.5 Hz, 3H), 2.25 (d, J=8.7 Hz, 1H), 1.11 (d, J=7.0Hz, 3H), 0.89 (d, J=6.9 Hz, 3H). ESI-MS m/z 305.22 (M+1)⁺.

Step 3. General Procedure

A mixture of(7S)-2-((trans-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride (1 equiv), a halogen substituted aromatic orheteroaromatic ring (1.1 equiv), and diisopropylethylamine (5 equiv) wastaken into 2 ml of isopropanol and heated in a microwave tube for 1 hourat 250 C. The reaction was evaporated in vacuo and purified by prepcolumn chromatography (C18) eluting with 0 to 100% acetonitrile/water(TFA modifier).

Examples prepared by the general procedure described above via reactionof Intermediate A-1(R₃=Me) or A-9 (R₃=iPr) are provided in Table 32.

TABLE 32 Comp. No. Ring B R3 [α]_(D) M + 1 485

Me 407.29 527

iPr 41.9 c = 1.0 DMSO 451.33 528

iPr 18.9 c = 1.0 DMSO 451.4 532

iPr 27.6 c = 1.0 DMSO 449.87 534

iPr 449.91 536

iPr 36.1 c = 1.0 DMSO 448.91 539

iPr 451.25 552

iPr 18.1 c = 1.0 DMSO 423.71 556

iPr 451.22 561

iPr 450.21 562

Me 421.87 569

iPr 454.28 576

iPr 465.87 577

Me 437.9 586

iPr 88.7 c = 1.0 DMSO 450.28 602

iPr 53.2 c = 1.0 407.97 715

iPr 425.29 716

iPr 22.6 c = 1.0 DMSO 407.29 717

iPr 6.2 c = 1.0 DMSO 408.3 732

iPr 400.31 733

iPr 412.35 734

iPr 451.32

Compound 485.(S)-4,7,8-trimethyl-2-((cis-3-((3,4,5-trifluorophenyl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 6.40-6.26 (m, 2H), 4.30 (q, J=6.9 Hz,1H), 4.21 (dd, J=16.1, 8.1 Hz, 1H), 3.72-3.59 (m, 1H), 3.26 (s, 3H),2.95 (dq, J=10.7, 7.2 Hz, 2H), 2.30 (s, 3H), 1.96 (dd, J=19.6, 8.9 Hz,2H), 1.53 (d, J=7.0 Hz, 3H).

Compound 527.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((4-(trifluoromethyl)pyrimidin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.57 (d, J=5.4 Hz, 1H), 7.04 (d, J=5.4Hz, 1H), 4.37-4.19 (m, 2H), 4.16 (d, J=3.8 Hz, 1H), 3.30 (d, J=3.5 Hz,3H), 3.05-2.83 (m, 2H), 2.41-2.33 (m, 1H), 2.34-2.28 (m, 3H), 2.22-2.08(m, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 528.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((6-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.69 (s, 1H), 7.08 (s, 1H), 4.42 (dd,J=22.5, 14.8 Hz, 1H), 4.37-4.22 (m, 1H), 4.16 (d, J=3.8 Hz, 1H), 3.29(s, 3H), 3.00 (dt, J=12.3, 6.3 Hz, 2H), 2.35 (ddd, J=12.3, 6.2, 3.1 Hz,1H), 2.31 (s, 3H), 2.26-2.15 (m, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H).

Compound 532.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((6-(trifluoromethyl)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.56 (t, J=7.9 Hz, 1H), 6.90 (d, J=7.2Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 4.19 (dt, J=12.0, 5.3 Hz, 2H), 4.14 (t,J=4.4 Hz, 1H), 3.29 (s, 3H), 3.04-2.84 (m, 2H), 2.40-2.30 (m, 1H), 2.30(s, 3H), 2.08-1.90 (m, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz,3H).

Compound 534.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 8.05 (dd, J=9.5, 1.9 Hz,1H), 7.15 (d, J=9.4 Hz, 1H), 4.42-4.29 (m, 1H), 4.16 (d, J=3.8 Hz, 1H),4.11 (td, J=8.5, 4.3 Hz, 1H), 3.19-3.03 (m, 2H), 2.35 (ddd, J=13.4, 6.7,3.6 Hz, 1H), 2.32-2.29 (m, 3H), 2.29-2.18 (m, 2H), 1.11 (d, J=7.0 Hz,3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 536.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((3,4,5-trifluorobenzyl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.49-7.36 (m, 2H), 4.40 (p, J=8.4 Hz,1H), 4.18 (s, 2H), 4.16 (d, J=3.8 Hz, 1H), 3.69 (p, J=8.3 Hz, 1H), 3.28(s, 3H), 2.98-2.84 (m, 2H), 2.51-2.42 (m, 2H), 2.38-2.33 (m, 1H), 2.31(d, J=2.9 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 539.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((2-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 6.79 (d, J=6.4 Hz, 1H),4.42 (s, 1H), 4.29 (dd, J=16.0, 8.1 Hz, 1H), 4.16 (d, J=3.8 Hz, 1H),2.98 (s, 2H), 2.41-2.32 (m, 1H), 2.31 (s, 3H), 2.17 (dd, J=17.0, 8.3 Hz,2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 552.(S)-4,7,8-trimethyl-2-((cis-3-((6-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.64 (s, 1H), 7.02 (s, 1H), 4.52-4.35(m, 1H), 4.35-4.29 (m, 1H), 4.29-4.20 (m, 1H), 3.27 (s, 3H), 2.99 (dt,J=11.0, 6.8 Hz, 2H), 2.33 (s, 3H), 2.18 (dd, J=19.0, 9.2 Hz, 2H), 1.53(d, J=6.9 Hz, 3H).

Compound 556.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((6-(trifluoromethyl)pyridazin-3-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.87 (d, J=9.6 Hz, 1H), 7.45 (d, J=9.6Hz, 1H), 4.34 (p, J=8.7 Hz, 1H), 4.20 (dd, J=14.9, 7.5 Hz, 1H), 4.17 (t,J=3.2 Hz, 1H), 3.30 (s, 3H), 3.17-3.01 (m, 2H), 2.42-2.34 (m, 1H), 2.32(d, J=4.0 Hz, 3H), 2.28-2.15 (m, 2H), 1.12 (d, J=7.0 Hz, 3H), 0.89 (d,J=6.9 Hz, 3H).

Compound 561.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((4-(trifluoromethyl)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.08 (d, J=6.8 Hz, 1H), 7.40 (d, J=0.7Hz, 1H), 7.11 (dd, J=6.8, 1.5 Hz, 1H), 4.46-4.31 (m, 1H), 4.15 (dd,J=10.4, 4.6 Hz, 1H), 4.14-4.03 (m, 1H), 3.30 (s, 3H), 3.20-3.03 (m, 2H),2.39 (ddd, J=10.1, 9.0, 3.3 Hz, 1H), 2.32 (s, 3H), 2.28-2.18 (m, 1H),1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 562.(S)-4,7,8-trimethyl-2-((cis-3-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.98 (dd, J=9.4, 2.1 Hz,1H), 7.09 (t, J=11.5 Hz, 1H), 4.40-4.26 (m, 2H), 4.14 (p, J=8.4 Hz, 1H),3.26 (d, J=4.0 Hz, 3H), 3.14-2.98 (m, 2H), 2.32 (s, 3H), 2.27-2.14 (m,2H), 1.53 (d, J=7.0 Hz, 3H).

Compound 569.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((1-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 4.18 (d, J=8.2 Hz, 1H), 4.15 (d, J=3.8Hz, 1H), 4.00 (tt, J=8.9, 7.2 Hz, 1H), 3.64 (s, 3H), 3.29 (s, 3H), 2.95(tdd, J=7.2, 5.7, 4.1 Hz, 2H), 2.35 (dd, J=7.2, 4.1 Hz, OH), 2.30 (s,3H), 2.20-2.01 (m, 1H), 1.11 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 576.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethoxy)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.05 (d, J=2.6 Hz, 1H), 7.99-7.84 (m,1H), 7.14 (dd, J=9.9, 0.7 Hz, 1H), 4.40-4.25 (m, 1H), 4.16 (d, J=3.8 Hz,1H), 4.04 (ddd, J=8.7, 7.1, 1.5 Hz, 1H), 3.29 (s, 3H), 3.13-2.97 (m,2H), 2.41-2.33 (m, 1H), 2.31 (s, 3H), 2.23 (ddd, J=11.8, 6.0, 2.8 Hz,1H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 577.(S)-4,7,8-trimethyl-2-((cis-3-((5-(trifluoromethoxy)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.05 (d, J=2.6 Hz, 1H), 7.99-7.82 (m,1H), 7.11 (d, J=9.8 Hz, 1H), 4.35-4.24 (m, 2H), 4.11-4.01 (m, 1H), 3.27(s, 3H), 3.08 (dt, J=11.2, 6.9 Hz, 2H), 2.32 (s, 3H), 2.26-2.15 (m, 2H),1.53 (d, J=6.9 Hz, 3H).

Compound 586.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((6-(trifluoromethyl)pyridin-3-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.96 (d, J=2.7 Hz, 1H), 7.49 (d, J=8.6Hz, 1H), 6.99 (dd, J=8.6, 2.7 Hz, 1H), 4.23 (tt, J=9.0, 7.3 Hz, 1H),3.90 (d, J=4.4 Hz, 1H), 3.69 (tt, J=8.5, 7.0 Hz, 1H), 3.14 (s, 3H),3.00-2.84 (m, 2H), 2.22 (qd, J=7.0, 4.5 Hz, 1H), 2.17 (s, 3H), 1.84(dddd, J=11.7, 10.3, 8.8, 4.4 Hz, 1H), 1.03 (d, J=7.0 Hz, 3H), 0.86 (d,J=6.9 Hz, 3H).

Compound 602.5-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)amino)pyrazine-2-carbonitrile

¹H NMR (400 MHz, Methanol-d₄) δ 8.33 (d, J=1.4 Hz, 1H), 7.98 (d, J=1.4Hz, 1H), 4.32-4.19 (m, 2H), 4.15 (d, J=3.8 Hz, 1H), 3.29 (s, 3H),3.03-2.90 (m, 2H), 2.35 (dd, J=7.0, 3.8 Hz, OH), 2.31 (s, 3H), 2.19-1.95(m, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H).

Compound 715.5-fluoro-6-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)amino)nicotinonitrile

¹H NMR (400 MHz, Methanol-d₄) δ 8.22 (d, J=3.0 Hz, 1H), 7.78 (dd, J=7.9,3.0 Hz, 1H), 4.35-4.18 (m, 2H), 4.15 (d, J=3.8 Hz, 1H), 3.31 (s, 3H),2.94 (dt, J=12.6, 6.6 Hz, 2H), 2.37 (s, OH), 2.30 (s, 3H), 2.17-2.04 (m,2H), 1.11 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 716.6-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)amino)nicotinonitrile

¹H NMR (400 MHz, Methanol-d₄) δ 8.46 (d, J=2.0 Hz, 1H), 8.00 (d, J=9.5Hz, 1H), 7.12 (d, J=9.5 Hz, 1H), 4.40-4.28 (m, 1H), 4.15 (dd, J=6.7, 2.6Hz, 1H), 4.14-4.04 (m, 1H), 3.12-3.02 (m, 2H), 2.31 (s, 3H), 2.28-2.19(m, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 717.2-((cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)amino)pyrimidine-5-carbonitrile

¹H NMR (400 MHz, Methanol-d₄) δ 8.59 (s, 1H), 8.53 (s, 1H), 4.37-4.18(m, 2H), 4.15 (d, J=3.8 Hz, 1H), 3.28 (s, 3H), 2.97-2.84 (m, 2H), 2.34(td, J=7.0, 3.9 Hz, OH), 2.30 (s, 3H), 2.16-2.05 (m, 2H), 1.11 (d, J=7.0Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 732.(S)-2-((cis-3-((5-fluoropyridin-2-yl)amino)cyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.99-7.93 (m, 2H), 7.15-7.08 (m, 1H),4.33 (m, 2H), 3.64-3.54 (m, 1H), 3.27 (d, J=1.4 Hz, 5H), 3.16-3.00 (m,3H), 2.29 (s, 3H), 1.11 (dd, J=6.9, 1.8 Hz, 3H), 0.90 (d, J=2.3 Hz, 3H).

Compound 733.(S)-7-isopropyl-2-((cis-3-((5-methoxypyridin-2-yl)amino)cyclobutyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.78-7.62 (m, 1H), 7.37 (dd, J=37.2, 2.8Hz, 1H), 7.02 (dd, J=19.0, 9.7 Hz, OH), 4.44-4.22 (m, 1H), 4.16 (t,J=3.1 Hz, 1H), 3.98 (q, J=8.0 Hz, 1H), 3.76 (t, J=7.4 Hz, 1H), 3.28 (s,3H), 3.11 (s, 2H), 2.93 (d, J=6.5 Hz, 1H), 2.30 (d, J=1.6 Hz, 3H), 1.11(d, J=6.8 Hz, 3H), 0.88 (d, J=2.0 Hz, 3H)

Compound 734.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.57 (s, 2H), 4.37-4.19 (m, 2H), 4.15(d, J=3.8 Hz, 1H), 3.29 (s, 3H), 3.02-2.89 (m, 2H), 2.42-2.32 (m, 1H),2.31 (s, 3H), 2.21-2.06 (m, 2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9Hz, 3H).

Example 2II General Scheme and Procedure for Examples in Table 33

Amide Formation (Methods A-D). Method A.

Diisopropylethylamine (4 equiv) was added to a solution of(7S)-2-((cis-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride (1 equiv), carboxylic acid derivative (1.5 equiv), andHATU (1.5 equiv) in NMP (2 ml) and stirred at room temperature. Thereaction was purified by reverse chromatography (C18) eluting withacetonitrile/water (TFA modifier).

Method B.

An acid chloride or chloroformate derivative (1.3 equiv) was added to asolution of(7S)-2-((cis-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride (1 equiv) in pyridine (1 ml) and stirred at roomtemperature for 1 hour. The reaction was evaporated in vacuo and theresidue purified by reverse chromatography (C18) eluting withacetonitrile/water (TFA modifier).

Method C.

A solution of phosgene (15% w/w, 800 μL) in toluene was added to amixture of(7S)-2-((cis-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride and diisopropylethylamine (0.5 ml, 2.89 mmol) indichloromethane (4 ml) and the reaction as stirred for 30 mins. Thereaction was evaporated in vacuo to afford the crude isocyantederivative. The amine (3 equiv) was added to a solution of the isocyante(1 equiv) and diisopropylethylamine (7 equiv) in dichloromethane (3 ml)and heated at 50 C overnight. Reaction was evaporated in vacuo andpurified by reverse phase chromatography (C18) eluting withacetonitrile/water (0.5% TFA)

Method D.

1-fluoro-4-isocyantobenzene (35 μL, 0.31 mmol) was added to a solutionof(7S)-2-((cis-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride (91 mg, 0.25 mmol) and diisopropylethylamine (175 μL,1.02 mmol) in isopropanol (2 ml). The reaction stirred at roomtemperature for 1 hour then evaporated in vacupo and the residue waspurified by reverse phase chromatography (C18) eluting withacetonitrile/water (0.5% TFA). To afford 67 mg of the desired product.

Table 33 examples were prepared by the general procedure described abovevia reaction of(7S)-2-((cis-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(R₃=iPr) or(7S)-2-((cis-3-aminocyclobutyl)amino)-7-methyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(R₃═CH₃) and one of the following: acyl chloride, sulfonyl chloride,chloroformate or isocyante.

TABLE 33 Comp. No. L₂-Ring B R₃ [α]_(D) M + 1 475

Me 435.29 514

iPr 34.5 c = 1.0 DMSO 477.25 553

iPr 35 c = 1.0 DMSO 480.84 559

iPr 491.81 481

Me 20.1 c = 1.0 DMSO 471.27 458

Me 19.4 c = 1.0 DMSO 414.17 460

Me 450.37 462

Me 18.9 c = 1.0 DMSO 431.34 464

Me 15.4 c = 1.0 DMSO 415.28 472

Me 450.28 484

Me 451.14 473

Me 19.3 c = 1.0 DMSO 465.33 477

Me 18.1 c = 1.0 DMSO 450.32 525

iPr 30.2 c = 1.0 DMSO 452.39 526

iPr 31.5 c = 1.0 DMSO 466.44 538

iPr 480.35

Compound 475.3,4,5-trifluoro-N-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)benzamide

¹H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J=6.6 Hz, 1H), 7.74-7.59 (m,2H), 4.31 (q, J=6.9 Hz, 1H), 4.27-4.16 (m, 2H), 3.26 (s, 3H), 2.97-2.79(m, 2H), 2.32 (s, 3H), 2.25-2.11 (m, 2H), 1.53 (d, J=7.0 Hz, 3H).

Compound 514.N-(cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-2-(3,4,5-trifluorophenyl)acetamide

¹H NMR (400 MHz, Methanol-d4) δ 7.11-6.99 (m, 2H), 4.23-4.16 (m, 1H),4.14 (d, J=3.8 Hz, 1H), 4.09-3.97 (m, 1H), 3.48 (s, 2H), 3.26 (s, 3H),2.88-2.77 (m, 2H), 2.40-2.31 (m, 1H), 2.30 (s, 3H), 2.13-1.99 (m, 2H),1.10 (t, J=7.5 Hz, 3H), 1.07-0.97 (m, 1H), 0.88 (d, J=6.9 Hz, 3H).

Compound 553

¹H NMR (400 MHz, Methanol-d4) δ 7.79 (dd, J=2.3, 0.9 Hz, 1H), 6.62 (d,J=2.3 Hz, 1H), 4.92 (s, 2H), 4.20 (dd, J=15.9, 8.1 Hz, 1H), 4.14 (t,J=4.2 Hz, 1H), 4.07 (dd, J=9.0, 7.5 Hz, 1H), 3.27 (s, 3H), 2.92-2.76 (m,2H), 2.42-2.30 (m, 1H), 2.30 (s, 3H), 2.17-1.97 (m, 2H), 1.11 (d, J=7.0Hz, 3H), 0.88 (d, J=6.9 Hz, 3H).

Compound 559.N-(cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide

¹H NMR (400 MHz, Methanol-d4) δ 8.61 (t, J=7.3 Hz, 1H), 7.97 (dd, J=8.1,1.5 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 4.14 (d, J=3.8 Hz, 1H), 4.04 (td,J=9.1, 4.5 Hz, 1H), 3.64 (d, J=10.1 Hz, 2H), 3.27 (d, J=5.6 Hz, 3H),2.94-2.69 (m, 2H), 2.43-2.30 (m, 1H), 2.29 (s, 3H), 2.12-1.94 (m, 2H),1.10 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H).

Compound 481.3,4,5-trifluoro-N-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)benzenesulfonamide

¹H NMR (400 MHz, Methanol-d4) δ 7.74-7.50 (m, 2H), 4.27 (q, J=6.9 Hz,1H), 4.13-3.99 (m, 1H), 3.68-3.52 (m, 1H), 3.20 (s, 3H), 2.73-2.56 (m,2H), 2.27 (s, 3H), 1.96-1.81 (m, 2H), 1.50 (d, J=6.9 Hz, 3H).

Compound 458.1-(4-fluorophenyl)-3-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (Methanol-d4) δ 7.41-7.27 (m, 2H), 6.98 (t, J=8.5 Hz, 2H), 4.30(d, J=6.7 Hz, 1H), 4.13 (s, 1H), 4.04-3.90 (m, 1H), 3.24 (s, 3H), 2.84(d, J=3.5 Hz, 2H), 2.30 (s, 3H), 2.07-1.94 (m, 2H), 1.52 (d, J=6.7 Hz,3H)

Compound 460.1-(2,3,4-trifluorophenyl)-3-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 7.66 (dddd, J=9.4, 8.1, 5.2, 2.6 Hz,1H), 7.03 (tdd, J=10.3, 8.2, 2.4 Hz, 1H), 4.30 (q, J=6.9 Hz, 1H),4.22-4.07 (m, 1H), 4.07-3.92 (m, 1H), 3.25 (s, 3H), 2.92-2.78 (m, 2H),2.31 (s, 3H), 2.09-1.93 (m, 2H), 1.53 (d, J=7.0 Hz, 3H).

Compound 462.1-(6-chloropyridin-3-yl)-3-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (300 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.95 (s, 1H), 7.42 (d,J=6.9 Hz, 1H), 4.41-3.93 (m, 3H), 3.25 (s, 3H), 2.85 (s, 2H), 2.66 (s,1H), 2.31 (s, 3H), 2.03 (s, 2H), 1.52 (s, 3H).

Compound 464. 4-fluorophenyl(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamate

¹H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.49 (s, 1H), 8.38 (s, 3H),8.18 (s, 1H), 4.66 (d, J=6.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 1H), 3.73 (t,J=10.8 Hz, 1H), 3.57 (s, 1H), 2.27 (s, 3H), 1.41 (d, J=6.9 Hz, 3H).

Compound 472.1-(3,4,5-trifluorophenyl)-3-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 7.24-7.10 (m, 2H), 4.37-4.21 (m, 1H),4.14 (dd, J=15.8, 7.9 Hz, 1H), 3.99 (dt, J=16.4, 4.5 Hz, 1H), 3.25 (s,3H), 2.85 (ddd, J=14.6, 7.1, 3.8 Hz, 2H), 2.31 (s, 3H), 2.02 (dt,J=16.9, 5.1 Hz, 2H), 1.53 (d, J=6.9 Hz, 3H).

Compound 484. 3,4,5-trifluorophenyl(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamate

¹H NMR (400 MHz, Methanol-d4) δ 7.08-6.79 (m, 2H), 4.30 (q, J=6.9 Hz,1H), 4.23-4.04 (m, 1H), 3.99-3.77 (m, 1H), 3.25 (s, 3H), 2.85 (dt,J=11.1, 7.1 Hz, 2H), 2.30 (s, 3H), 2.10 (dd, J=19.6, 9.0 Hz, 2H), 1.53(d, J=7.0 Hz, 3H).

Compound 473.1-(6-(trifluoromethyl)pyridin-3-yl)-3-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=2.5 Hz, 1H), 8.14-8.04 (m,1H), 7.69 (d, J=8.6 Hz, 1H), 4.30 (q, J=6.9 Hz, 1H), 4.24-4.12 (m, 1H),4.11-3.95 (m, 1H), 3.26 (s, 3H), 2.92-2.79 (m, 2H), 2.31 (s, 3H), 2.07(dtd, J=10.4, 9.1, 1.4 Hz, 2H), 1.53 (d, J=7.0 Hz, 3H).

Compound 477.1-(2,4,5-trifluorophenyl)-3-(cis-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 8.08-7.87 (m, 1H), 7.17 (td, J=10.5, 7.3Hz, 1H), 4.30 (q, J=6.9 Hz, 1H), 4.22-4.10 (m, 1H), 4.08-3.89 (m, 1H),3.25 (s, 3H), 2.92-2.77 (m, 2H), 2.31 (s, 3H), 2.10-1.94 (m, 2H), 1.53(d, J=7.0 Hz, 3H).

Compound 525.4,4-difluoro-N-(cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)piperidine-1-carboxamide

¹H NMR (400 MHz, Methanol-d4) δ 4.37-4.27 (m, 1H), 4.20 (d, J=3.8 Hz,1H), 4.03-3.89 (m, 1H), 3.77-3.68 (m, 4H), 3.51 (dd, J=14.3, 8.5 Hz,4H), 3.26 (s, 3H), 2.92-2.76 (m, 2H), 2.40 (s, 3H), 2.34 (dtd, J=10.8,6.9, 3.5 Hz, 1H), 2.21-2.05 (m, 6H), 1.93 (ddd, J=19.6, 13.6, 5.8 Hz,4H), 1.12 (d, J=6.9 Hz, 3H), 0.89 (dd, J=6.8, 4.0 Hz, 3H).

Compound 526.1-(4,4-difluorocyclohexyl)-3-(cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 4.30-4.21 (m, 1H), 4.14 (t, J=3.9 Hz,1H), 3.92 (dt, J=14.9, 6.2 Hz, 1H), 3.81 (t, J=9.7 Hz, 1H), 3.61 (t,J=9.6 Hz, 1H), 3.25 (s, 3H), 3.02-2.88 (m, 2H), 1.92 (ddd, J=14.3, 9.9,6.9 Hz, 9H), 1.72-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.09 (d, J=7.0 Hz,3H), 0.87 (dd, J=14.9, 6.9 Hz, 3H).

Compound 538.1-(4,4-difluorocyclohexyl)-3-(cis-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-1-methylurea

¹H NMR (400 MHz, Methanol-d4) δ 4.15 (d, J=3.8 Hz, 1H), 4.09 (d, J=8.5Hz, 1H), 4.04-3.91 (m, 1H), 3.27 (s, 3H), 2.89-2.77 (m, 2H), 2.75 (s,3H), 2.41-2.31 (m, 1H), 2.29 (s, 3H), 2.05 (dddd, J=13.1, 9.2, 7.9, 5.0Hz, 4H), 1.94-1.71 (m, 4H), 1.65 (d, J=9.3 Hz, 2H), 1.11 (d, J=7.0 Hz,3H), 0.89 (d, J=6.9 Hz, 3H).

Example 2JJ General Scheme and Procedure for Examples in Table 34

Step 1

tert-Butyl(trans-3-(((7S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamateand tert-Butyl(trans-3-(((7S)-7-methyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamatewere prepared and deprotected to(7S)-2-((trans-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride and(7S)-2-((trans-3-aminocyclobutyl)amino)-7-methyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride via the same procedure as described for scheme and Table32.

The examples in Table 34 were prepared via the same procedures describedfor Table 33.

TABLE 34 Comp. No. L₂-Ring B R₃ Op rotation M + 1 476

Me 14.5 c = 1.0 DMSO 435.29 515

iPr 477.28 554

iPr 480.87 560

iPr 491.81 482

Me 471.2 459

Me 414.2 461

Me 450.14 463

Me 431.27 465

Me 415.28 474

Me 450.32 483

Me 451.14 471

Me 465.29 478

Me 450.32 523

iPr 452.39 524

iPr 466.44 537

iPr 480.24

Compound 476.3,4,5-trifluoro-N-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)benzamide

¹H NMR (400 MHz, Methanol-d4) δ 8.87 (d, J=6.3 Hz, 1H), 7.76-7.60 (m,2H), 4.65-4.48 (m, 2H), 4.30 (q, J=6.9 Hz, 1H), 3.25 (s, 3H), 2.65-2.48(m, 4H), 2.33 (s, 3H), 1.53 (d, J=6.9 Hz, 3H).

Compound 515.N-(trans-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-2-(3,4,5-trifluorophenyl)acetamide

¹H NMR (400 MHz, Methanol-d4) δ 7.15-6.99 (m, 2H), 4.50 (p, J=6.4 Hz,1H), 4.41-4.31 (m, 1H), 4.15 (d, J=3.8 Hz, 1H), 3.51 (s, 2H), 3.26 (s,3H), 2.53-2.40 (m, 4H), 2.37-2.31 (m, 1H), 2.31 (d, J=4.2 Hz, 3H),1.15-1.06 (m, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 554.N-(trans-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamide

¹H NMR (400 MHz, Methanol-d4) δ 7.80 (dd, J=2.3, 0.9 Hz, 1H), 6.62 (d,J=2.1 Hz, 1H), 4.95 (s, 2H), 4.52 (p, J=6.5 Hz, 1H), 4.45-4.35 (m, 1H),4.15 (d, J=3.8 Hz, 1H), 3.27 (s, 3H), 2.50 (dd, J=11.4, 6.1 Hz, 4H),2.36 (ddd, J=10.0, 8.8, 5.0 Hz, 1H), 2.31 (d, J=5.0 Hz, 3H), 1.11 (d,J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 560.N-(trans-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide

¹H NMR (400 MHz, Methanol-d4) δ 8.64 (d, J=1.8 Hz, 1H), 7.98 (dd, J=8.1,1.5 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 4.56-4.44 (m, 1H), 4.42-4.32 (m,1H), 4.14 (d, J=3.8 Hz, 1H), 3.76-3.63 (m, 2H), 3.26 (s, 3H), 2.47 (dd,J=10.3, 6.6 Hz, 4H), 2.40-2.31 (m, 1H), 2.30 (s, 3H), 1.78-1.54 (m, 2H),1.09 (dd, J=10.6, 5.1 Hz, 3H), 0.89 (t, J=7.7 Hz, 3H).

Compound 482.3,4,5-trifluoro-N-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)benzenesulfonamide

¹H NMR (400 MHz, Methanol-d4) δ 7.70-7.54 (m, 2H), 4.42-4.32 (m, 1H),4.28 (q, J=6.9 Hz, 1H), 3.95 (p, J=6.8 Hz, 1H), 3.20 (s, 3H), 2.32 (td,J=6.8, 2.6 Hz, 4H), 2.29 (d, J=6.9 Hz, 3H), 1.51 (d, J=6.9 Hz, 3H)

Compound 459.1-(4-fluorophenyl)-3-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.49 (s, 1H), 8.38 (s, 3H),8.18 (s, 1H), 4.66 (d, J=6.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 1H), 3.73 (t,J=10.8 Hz, 1H), 3.57 (s, 1H), 2.27 (s, 3H), 1.41 (d, J=6.9 Hz, 3H).

Compound 461.1-(2,3,4-trifluorophenyl)-3-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 7.66 (dddd, J=9.4, 8.1, 5.2, 2.6 Hz,1H), 7.03 (tdd, J=10.2, 8.2, 2.4 Hz, 1H), 4.52-4.42 (m, 1H), 4.40-4.17(m, 2H), 3.24 (s, 3H), 2.53-2.39 (m, 4H), 2.32 (s, 3H), 1.53 (d, J=7.0Hz, 3H).

Compound 463.1-(6-chloropyridin-3-yl)-3-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (300 MHz, Methanol-d4) δ 8.45 (d, J=2.4 Hz, 1H), 7.93 (dd, J=8.7,2.8 Hz, 1H), 7.37 (d, J=8.7 Hz, 1H), 4.53-4.40 (m, 1H), 4.33 (dq,J=17.6, 6.9 Hz, 2H), 3.24 (s, 3H), 2.47 (t, J=6.7 Hz, 4H), 2.31 (s, 3H),1.52 (d, J=6.9 Hz, 3H).

Compound 465. 4-fluorophenyl(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamate

¹H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.49 (s, 1H), 8.38 (s, 3H),8.18 (s, 1H), 4.66 (d, J=6.2 Hz, 1H), 4.30 (q, J=6.8 Hz, 1H), 3.73 (t,J=10.8 Hz, 1H), 3.57 (s, 1H), 2.27 (s, 3H), 1.41 (d, J=6.9 Hz, 3H).

Compound 474.1-(3,4,5-trifluorophenyl)-3-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 7.27-7.11 (m, 2H), 4.43 (s, 1H), 4.31(dt, J=20.7, 7.1 Hz, 2H), 3.23 (s, 3H), 2.46 (dd, J=11.4, 4.4 Hz, 4H),2.31 (s, 3H), 1.52 (d, J=6.9 Hz, 3H).

Compound 483. 3,4,5-trifluorophenyl(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)carbamate

¹H NMR (400 MHz, Methanol-d4) δ 7.07-6.89 (m, 2H), 4.48 (dd, J=12.4, 6.7Hz, 1H), 4.35-4.28 (m, 1H), 4.27-4.19 (m, 1H), 3.25 (s, 3H), 2.59-2.41(m, 4H), 2.31 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).

Compound 471.1-(6-(trifluoromethyl)pyridin-3-yl)-3-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 8.70 (d, J=2.5 Hz, 1H), 8.17-8.02 (m,1H), 7.69 (d, J=8.6 Hz, 1H), 4.48 (p, J=6.4 Hz, 1H), 4.42-4.34 (m, 1H),4.34-4.23 (m, 1H), 3.25 (d, J=4.8 Hz, 3H), 2.49 (t, J=6.8 Hz, 4H), 2.32(s, 3H), 1.53 (d, J=7.0 Hz, 3H).

Compound 478.1-(2,4,5-trifluorophenyl)-3-(trans-3-(((S)-4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 8.15-7.91 (m, 1H), 7.18 (td, J=10.6, 7.3Hz, 1H), 4.56-4.39 (m, 1H), 4.40-4.24 (m, 2H), 3.24 (s, 3H), 2.58-2.36(m, 4H), 2.32 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).

Compound 523.4,4-difluoro-N-(trans-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)piperidine-1-carboxamide

¹H NMR (400 MHz, Methanol-d4) δ 4.40 (s, 1H), 4.31 (dd, J=14.5, 6.7 Hz,1H), 4.14 (d, J=3.9 Hz, 1H), 3.57-3.47 (m, 4H), 3.26 (s, 3H), 2.65 (s,2H), 2.50-2.39 (m, 4H), 2.35-2.31 (m, 1H), 2.30 (s, 3H), 1.94 (ddd,J=19.6, 13.7, 5.8 Hz, 4H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz,3H).

Compound 524.1-(4,4-difluorocyclohexyl)-3-(trans-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)urea

¹H NMR (400 MHz, Methanol-d4) δ 4.39 (s, 1H), 4.32-4.22 (m, 1H), 4.14(d, J=3.8 Hz, 1H), 3.63 (t, J=9.7 Hz, 1H), 3.32 (dd, J=3.3, 1.7 Hz, 1H),3.26 (s, 3H), 2.46-2.32 (m, 4H), 2.29 (s, 3H), 2.00 (t, J=11.9 Hz, 2H),1.86 (ddd, J=28.9, 12.5, 4.0 Hz, 4H), 1.62-1.37 (m, 2H), 1.11 (d, J=7.0Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 537.1-(4,4-difluorocyclohexyl)-3-(trans-3-(((S)-7-isopropyl-4,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)cyclobutyl)-1-methylurea

¹H NMR (400 MHz, Methanol-d4) δ 4.45-4.32 (m, 2H), 4.17 (d, J=11.7 Hz,1H), 4.14 (s, 1H), 3.25 (d, J=4.9 Hz, 3H), 2.77 (s, 3H), 2.45 (dddd,J=13.9, 11.3, 7.6, 3.3 Hz, 4H), 2.36-2.31 (m, 1H), 2.30 (s, 3H),2.17-2.05 (m, 2H), 2.01-1.91 (m, 1H), 1.89-1.74 (m, 3H), 1.67 (s, 2H),1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Example 2KK General Scheme and Procedure for Preparation of Examples inTable 35

General Procedure.

A mixture of(7S)-2-((trans-3-aminocyclobutyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-onedihydrochloride (1 equiv), a halogen substituted aromatic orheteroaromatic ring (1.1 equiv), and diisopropylethylamine (5 equiv) wastaken into 2 ml of isopropanol and heated in a microwave tube for 1 hourat 150 C. The reaction was evaporated in vacuo and purified by prepcolumn chromatography (C18) eluting with 0 to 100% acetonitrile/water(TFA modifier).

TABLE 35 Comp. No. Ring B R₃ [α]_(D) M + 1 486

Me 407.36 529

iPr 451.4 530

iPr 42.0 c = 1.0 DMSO 451.4 531

iPr 449.87 533

iPr 449.71 535

iPr 448.91 540

iPr 451.25 555

iPr 47.4 c = 1.0 DMSO 451.25 558

iPr 39.4 c = 1.0 DMSO 451.18 579

Me 15.6 c = 1.0 DMSO 422.9 587

iPr 25.0 c = 1.0 DMSO 450.28

Compound 486.(S)-4,7,8-trimethyl-2-((trans-3-((3,4,5-trifluorophenyl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 6.37-6.28 (m, 2H), 4.61-4.49 (m, 1H),4.29 (q, J=6.9 Hz, 1H), 4.02-3.92 (m, 1H), 3.23 (s, 3H), 2.58-2.36 (m,4H), 2.31 (s, 3H), 1.52 (d, J=7.0 Hz, 3H).

Compound 529.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((4-(trifluoromethyl)pyrimidin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.56 (d, J=5.3 Hz, 1H), 7.03 (d, J=5.3Hz, 1H), 4.57 (dd, J=12.0, 6.1 Hz, 2H), 4.15 (d, J=3.8 Hz, 1H), 3.27 (s,3H), 2.58 (dd, J=11.4, 6.3 Hz, 4H), 2.38-2.34 (m, 1H), 2.32 (d, J=3.1Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 530.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.61 (s, 1H), 7.04 (s, 1H), 4.62 (dt,J=13.9, 7.5 Hz, 2H), 4.15 (d, J=3.8 Hz, 1H), 3.28 (s, 3H), 2.71-2.45 (m,4H), 2.36 (ddd, J=8.5, 8.1, 4.2 Hz, 1H), 2.32 (s, 3H), 1.11 (d, J=7.0Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 531.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.56 (t, J=7.9 Hz, 1H), 6.89 (t, J=8.3Hz, 1H), 6.67 (d, J=8.6 Hz, 1H), 4.49 (dd, J=12.3, 6.7 Hz, 2H), 4.14 (d,J=3.8 Hz, 1H), 3.26 (d, J=6.9 Hz, 3H), 2.57-2.44 (m, 4H), 2.39-2.32 (m,1H), 2.30 (d, J=3.5 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz,3H).

Compound 533.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((5-(trifluoromethyl)pyridin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 8.04 (dd, J=9.5, 2.1 Hz,1H), 7.20 (d, J=9.4 Hz, 1H), 4.77-4.62 (m, 1H), 4.49-4.36 (m, 1H), 4.16(d, J=3.8 Hz, 1H), 3.28 (d, J=6.5 Hz, 3H), 2.75 (td, J=14.0, 7.5 Hz,2H), 2.65 (ddt, J=11.9, 7.8, 3.8 Hz, 2H), 2.36 (dt, J=5.1, 3.0 Hz, 1H),2.32 (s, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 535.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((3,4,5-trifluorobenzyl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.50-7.34 (m, 2H), 4.79-4.67 (m, 1H),4.19 (s, 2H), 4.16 (d, J=3.8 Hz, 1H), 4.08-3.94 (m, 1H), 3.28 (s, 3H),2.85-2.76 (m, 2H), 2.67-2.59 (m, 2H), 2.37-2.32 (m, 1H), 2.32 (d, J=6.8Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 540.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.18 (s, 1H), 6.87 (d, J=5.7 Hz, 1H),4.75 (s, 1H), 4.60 (s, 1H), 4.15 (d, J=3.8 Hz, 1H), 3.27 (s, 3H),2.70-2.53 (m, 4H), 2.38-2.32 (m, 1H), 2.32 (s, 3H), 1.11 (d, J=7.0 Hz,3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 555.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridazin-3-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.89 (d, J=9.6 Hz, 1H), 7.52 (d, J=9.6Hz, 1H), 4.69 (p, J=7.2 Hz, 1H), 4.53-4.39 (m, 1H), 4.15 (d, J=3.8 Hz,1H), 3.29 (d, J=7.5 Hz, 3H), 2.87-2.58 (m, 4H), 2.37 (ddd, J=11.2, 9.3,6.2 Hz, 1H), 2.32 (s, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz,3H).

Compound 558.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.25 (d, J=0.5 Hz, 1H), 8.15 (d, J=0.8Hz, 1H), 4.62 (dd, J=13.7, 6.8 Hz, 1H), 4.54-4.41 (m, 1H), 4.16 (d,J=3.8 Hz, 1H), 3.28 (s, 3H), 2.72-2.51 (m, 4H), 2.40-2.34 (m, 1H), 2.32(s, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H)

Compound 579.(S)-4,7,8-trimethyl-2-((trans-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.40-8.18 (m, 1H), 8.16 (d, J=1.3 Hz,1H), 4.61 (t, J=7.1 Hz, 1H), 4.48 (dtd, J=7.2, 3.4, 1.8 Hz, 1H), 4.30(q, J=6.9 Hz, 1H), 3.25 (s, 3H), 2.75-2.49 (m, 3H), 2.33 (s, 3H), 1.53(d, J=7.0 Hz, 3H)

Compound 587.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 7.98 (d, J=2.7 Hz, 1H), 7.50 (d, J=8.7Hz, 1H), 6.97 (dd, J=8.6, 2.7 Hz, 1H), 4.61 (t, J=7.1 Hz, 1H), 4.13 (d,J=3.8 Hz, 1H), 4.08 (s, 1H), 3.25 (s, 3H), 2.69-2.41 (m, 4H), 2.32 (s,3H), 1.11 (d, J=6.9 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Example 2LL General Scheme and Procedure for Preparation of Examples inTable 36

General Procedure for Examples in Table 36

The compounds were prepared via reaction of Intermediate A-# (1 equiv)andtrans-N1-methyl-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diaminehydrochloride (B-199) (1.2 equiv) via the procedure described forexamples in Table 27 to provide the desired products.

TABLE 36 Comp. No. R₃ Int A [α]_(D) M + 1 655 iPr A-9 81.2 c = 1.0465.32 DMSO 681 (R)—CH(OCH3)CH3 A-59 49.7 481.34 c = 1.0 DMSO 682 Et A-833.3 451.57 c = 1.0 DMSO 683 Me A-2 9.9 c = 1.0 437.56 DMSO

Compound 655.(7S)-7-isopropyl-4,8-dimethyl-2-((trans-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.38 (s, 1H), 8.00 (d,J=1.4 Hz, 1H), 5.16-4.94 (m, 2H), 4.35 (td, J=8.1, 4.2 Hz, 1H), 3.89 (d,J=4.4 Hz, 1H), 3.19 (s, 3H), 3.12 (s, 3H), 2.64 (dtd, J=11.9, 7.5, 3.7Hz, 2H), 2.43 (d, J=3.0 Hz, 1H), 2.23 (s, 3H), 1.08 (d, J=6.9 Hz, 3H),0.94 (d, J=6.9 Hz, 3H)

Compound 681.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((trans-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.37 (dd, J=1.5, 0.8 Hz, 1H), 8.27-8.15(m, 1H), 5.28-5.14 (m, 1H), 4.39 (d, J=8.4 Hz, 1H), 4.23 (d, J=3.9 Hz,1H), 3.80 (qd, J=6.5, 3.9 Hz, 1H), 3.33 (s, 3H), 3.29 (s, 3H), 3.23 (s,3H), 2.88-2.67 (m, 2H), 2.53 (dq, J=10.1, 6.4, 5.3 Hz, 2H), 2.34 (s,3H), 1.29 (d, J=6.5 Hz, 3H).

Compound 682.(S)-7-ethyl-4,8-dimethyl-2-((trans-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ8.37 (s, 1H), 8.19 (d, J=1.3 Hz, 1H),5.23 (p, J=8.2 Hz, 1H), 4.43 (ddt, J=16.9, 8.5, 4.2 Hz, 1H), 4.34 (dd,J=5.8, 3.4 Hz, 1H), 3.24 (2s, 6H), 2.90-2.76 (m, 2H), 2.54 (tt, J=7.9,3.5 Hz, 2H), 2.35 (s, 3H), 2.05 (tdd, J=21.1, 10.7, 5.3 Hz, 2H), 0.87(t, J=7.4 Hz, 3H).

Compound 683.(S)-4,7,8-trimethyl-2-((trans-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.36 (s, 1H), 8.18 (d, J=1.3 Hz, 1H),5.23 (t, J=8.2 Hz, 1H), 4.42 (td, J=8.4, 7.7, 4.1 Hz, 1H), 4.32 (q,J=6.9 Hz, 1H), 3.23 (s, 3H), 2.87-2.74 (m, 2H), 2.54 (tt, J=8.5, 3.7 Hz,2H), 2.36 (s, 3H), 1.54 (d, J=6.9 Hz, 3H).

Example 2MM General Scheme and Procedure for Preparation of Examples inTable 37

General Procedure for Examples in Table 37

The compounds were prepared via reaction of Intermediate A-# (1 equiv)andcis-N1-methyl-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diaminehydrochloride (B-198) (1.2 equiv) via the procedure described forexamples in Table 27 to provide the desired products.

TABLE 37 Comp. No. R₃ Int A [α]_(D) M + 1 652 iPr A-9 76.2 465.27 c = 10DMSO 653 Me A-2 40.2 437.22 c = 1.0 DMSO 651 (R)—CH(OCH3)CH3 A-59 65.2481.34 c = 1.0 DMSO 654 Et A-8 451.32

Compound 652.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 9.28 (s, 1H), 8.37 (d, J=1.3 Hz, 1H),8.03 (d, J=1.4 Hz, 1H), 4.96 (d, J=7.1 Hz, 1H), 4.52 (tt, J=9.5, 7.2 Hz,1H), 4.21 (dtd, J=8.9, 7.1, 1.8 Hz, 1H), 3.88 (d, J=4.4 Hz, 1H), 2.86(dtt, J=11.7, 5.7, 1.6 Hz, 2H), 2.23 (s, 3H), 2.08 (dtd, J=11.5, 9.3,2.1 Hz, 2H), 1.07 (d, J=7.0 Hz, 3H), 0.93 (d, J=7.0 Hz, 3H).

Compound 653.(S)-4,7,8-trimethyl-2-((cis-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.16 (s, 1H), 8.05 (d,J=1.5 Hz, 1H), 4.87 (d, J=7.1 Hz, 1H), 4.54 (tt, J=9.6, 7.2 Hz, 1H),4.31-4.17 (m, 1H), 4.09 (q, J=6.8 Hz, 1H), 3.14 (s, 3H), 3.07 (s, 3H),2.88 (dt, J=11.5, 6.9 Hz, 2H), 2.24 (s, 3H), 2.16-2.04 (m, 2H), 1.42 (d,J=6.8 Hz, 3H).

Compound 651.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((cis-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.47-8.31 (m, 1H), 8.04(d, J=1.4 Hz, 1H), 5.09 (d, J=7.1 Hz, 1H), 4.54 (tt, J=9.6, 7.2 Hz, 1H),4.22 (dtd, J=8.9, 7.1, 1.8 Hz, 1H), 3.95 (d, J=6.1 Hz, 1H), 3.58 (p,J=6.3 Hz, 1H), 3.20 (s, 3H), 3.13 (s, 3H), 2.92-2.83 (m, 2H), 2.25 (s,3H), 2.10 (dtd, J=13.1, 10.8, 10.1, 2.9 Hz, 2H), 1.25 (d, J=6.4 Hz, 3H).

Compound 654.(7S)-7-ethyl-4,8-dimethyl-2-((cis-3-(methyl(5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 8.44-8.34 (m, 1H), 8.21 (s, 1H), 8.05(d, J=1.5 Hz, 1H), 4.88 (d, J=7.2 Hz, 1H), 4.54 (tt, J=9.5, 7.2 Hz, 1H),4.34-4.19 (m, 1H), 4.08 (dd, J=6.5, 3.8 Hz, 1H), 3.14 (s, 3H), 3.09 (s,3H), 2.92-2.79 (m, 2H), 2.22 (s, 3H), 2.17-1.77 (m, 4H), 0.92 (t, J=7.5Hz, 3H)

Example 2NN General Procedure for Examples in Table 38

The compounds were prepared via reaction of Intermediate A-# (1 equiv)and cis-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diaminehydrochloride, B-209 (1.2 equiv) via the procedure described forexamples in Table L to provide the desired products.

TABLE 38 Comp. No. R₃ Int A [α]_(D) M + 1 557 iPr A-9 72.4 451.22 c =1.0 DMSO 578 Me A-2 14.9 422.9 c = 1.0 DMSO 647 (R)- A-59 39.5 467.24CH(OCH3) c = 1.0 CH3 DMSO 648 -Et A-8 435.19 672

A-66 493.27

Compound 557.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.27 (d, J=0.6 Hz, 1H), 7.99 (d, J=1.2Hz, 1H), 4.33-4.18 (m, 2H), 4.16 (d, J=3.8 Hz, 1H), 3.29 (s, 3H),3.03-2.85 (m, 2H), 2.38-2.31 (m, 1H), 2.31 (s, 3H), 2.16-2.00 (m, 2H),1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H).

Compound 578.(S)-4,7,8-trimethyl-2-((cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.31 (s, 1H), 8.28-8.13 (m, 1H),4.41-4.26 (m, 2H), 4.20 (tt, J=8.7, 7.2 Hz, 1H), 3.27 (s, 3H), 3.10-2.91(m, 2H), 2.33 (s, 3H), 2.22 (dtt, J=10.6, 7.1, 1.8 Hz, 2H), 1.53 (d,J=6.9 Hz, 3H).

Compound 647.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.35-8.20 (m, 1H), 8.04 (d, J=1.3 Hz,1H), 4.34-4.27 (m, 1H), 4.23 (d, J=3.9 Hz, 1H), 3.79 (tt, J=6.5, 3.2 Hz,1H), 3.35 (s, 3H), 3.29 (s, 3H), 2.99 (dddd, J=12.8, 7.0, 5.7, 1.7 Hz,2H), 2.31 (d, J=8.0 Hz, 3H), 2.21-2.04 (m, 2H), 1.29 (d, J=6.5 Hz, 3H)

Compound 648.(S)-7-ethyl-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.28 (s, 1H), 7.91 (d, J=1.5 Hz, 1H),4.33 (dd, J=5.7, 3.4 Hz, 1H), 4.23 (q, J=8.7, 7.3 Hz, 2H), 3.25 (s, 3H),2.97 (t, J=5.7 Hz, 2H), 2.30 (s, 3H), 2.11-1.99 (m, 1H), 0.86 (dd,J=7.5, 3.2 Hz, 3H).

Compound 672.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-((cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 6.94-6.79 (m, 2H), 6.69 (d,J=6.8 Hz, 1H), 4.84 (td, J=6.6, 3.3 Hz, 1H), 4.39 (dd, J=13.2, 6.4 Hz,1H), 4.21 (s, 1H), 3.10 (s, 3H), 3.06 (d, J=4.5 Hz, 3H), 2.40 (dd,J=13.8, 9.7 Hz, 1H), 2.37-2.28 (m, 2H), 2.23 (dd, J=9.0, 3.5 Hz, 1H),2.18-2.05 (m, 5H), 1.98 (dd, J=18.6, 8.9 Hz, 1H), 1.70 (ddd, J=20.2,10.2, 4.7 Hz, 1H), 1.56 (dt, J=9.0, 7.9 Hz, 1H).

Example 2OO General Procedure for Examples in Table 39

The compounds were prepared via reaction of Intermediate A-# (1 equiv)and cis-N1-(5-(trifluoromethyl)pyrazin-2-yl)cyclobutane-1,3-diaminehydrochloride, B-212 (1.2 equiv) via the procedure described forexamples in Table L to provide the desired products.

TABLE 39 Comp. No. R₃ Int A [α]_(D) M + 1 738 —Et A-8 451.29 737 —CH3A-2 437.29 736 (R)—CH(OCH3)CH3 A-59 481.31 735 iPr A-9 76.9 465.45 c =1.0 MeOH

Compound 738.(S)-7-ethyl-4,8-dimethyl-2-(((1R,3S)-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.29-8.22 (m, 1H), 8.20 (d, J=1.4 Hz,1H), 4.51-4.42 (m, 1H), 4.33 (dt, J=6.4, 3.3 Hz, 2H), 3.26 (s, 3H), 2.69(dt, J=14.2, 7.4 Hz, 1H), 2.31 (s, 3H), 2.23-2.18 (m, 1H), 2.12-2.00 (m,2H), 1.92-1.86 (m, 2H), 1.71 (dt, J=13.7, 6.9 Hz, 1H), 0.91-0.83 (m,3H).

Compound 737.(S)-4,7,8-trimethyl-2-(((1R,3S)-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ8.28-8.21 (m, 1H), 8.18 (d, J=1.3 Hz,1H), 4.44 (qd, J=6.9, 4.3 Hz, 1H), 4.36-4.25 (m, 2H), 3.26 (s, 3H),2.73-2.64 (m, 1H), 2.32 (s, 3H), 2.20 (td, J=6.6, 4.4 Hz, 2H), 1.93-1.86(m, 2H), 1.75-1.67 (m, 1H), 1.53 (dd, J=7.0, 2.0 Hz, 3H).

Compound 736.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-(((1R,3S)-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.31-8.22 (m, 1H), 8.11 (d, J=1.3 Hz,1H), 4.46-4.41 (m, 1H), 4.35-4.29 (m, 1H), 4.23 (d, J=3.9 Hz, 1H), 3.79(qd, J=6.4, 3.9 Hz, 1H), 3.35 (s, 3H), 3.30 (s, 3H), 2.74-2.64 (m, 1H),2.31 (s, 3H), 2.24-2.16 (m, 2H), 1.94-1.85 (m, 2H), 1.68 (dt, J=13.7,7.1 Hz, 1H), 1.29 (d, J=6.5 Hz, 3H).

Compound 735.(S)-7-isopropyl-4,8-dimethyl-2-(((1R,3S)-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.24 (t, J=1.0 Hz, 1H), 8.21 (d, J=1.3Hz, 1H), 4.44 (p, J=6.8 Hz, 1H), 4.36-4.29 (m, 1H), 4.15 (d, J=3.8 Hz,1H), 3.29 (s, 3H), 2.69 (dt, J=13.4, 7.4 Hz, 1H), 2.35 (ddd, J=10.9,7.0, 3.6 Hz, 1H), 2.31 (s, 3H), 2.25-2.16 (m, 2H), 1.96-1.84 (m, 2H),1.72 (dt, J=13.6, 6.9 Hz, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.90 (d, J=6.9Hz, 3H).

Example 2PP General Scheme and Procedure for Preparation of Examples inTable 40

General Procedure for Examples in Table 40

The compounds of Table 40 were prepared by the Method A procedure (seeCompound 46) via reaction of Intermediates A-# and B-101.

TABLE 40 Comp. R₃ = No. R₄ = [α]_(D) M + 1 745 R3 = (S)- 494.35CH(OtBu)CH₃ R4 = H 720 R₃ = -CH₃ −45.9 c = 0.5 452.27 R₄ = -CH₂OCH₃ MeOH719 R₃ = -CH₂OCH₃ 46.8 c = 0.7 452.27 R₄ = -CH₃ MeOH 677 R3 = -CH₂OH43.6 c = 0.5 424.8 R₄ = H DMSO 674 R₃ = -CH₂OtBu 46.4 c = 0.5 480.43 R₄= H CHCl3 667

9.6 c = 0.5 MeOH 478.19 599 R₃= (R)- 63.9 c = 1.0 452.31 CH(OCH₃)CH₃DMSO R₄ = H

Compound 745.(S)-7-((S)-1-(tert-butoxy)ethyl)-4,8-dimethyl-2-(((1r,3S)-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 6.43 (dd, J=9.2, 5.7 Hz, 2H), 4.79 (p,J=5.2 Hz, 1H), 4.59 (d, J=6.3 Hz, 1H), 4.21-4.07 (m, 3H), 4.04 (d, J=2.1Hz, 2H), 3.29 (s, 3H), 2.61 (s, 4H), 2.37 (s, 3H), 1.27 (d, J=6.4 Hz,3H), 1.10 (s, 9H).

Compound 720.7-(methoxymethyl)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 6.90-6.77 (m, 2H), 6.66 (s,1H), 4.83 (td, J=6.8, 3.5 Hz, 1H), 4.38 (q, J=6.8 Hz, 1H), 3.60 (dd,J=45.4, 10.0 Hz, 2H), 3.20 (s, 3H), 2.47-2.01 (m, 7H), 1.33 (s, 3H),1.29-1.15 (m, 3H).

Compound 719.7-(methoxymethyl)-4,7,8-trimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 6.91-6.77 (m, 2H), 6.66 (d,J=6.9 Hz, 1H), 4.84 (td, J=6.7, 3.4 Hz, 1H), 4.38 (q, J=6.9 Hz, 1H),3.66 (d, J=10.1 Hz, 1H), 3.54 (d, J=10.0 Hz, 1H), 3.20 (s, 3H), 2.96 (s,3H), 2.47-2.29 (m, 4H), 2.10 (s, 3H), 1.33 (s, 3H), 1.27-1.12 (m, 3H).

Compound 677.(S)-7-(hydroxymethyl)-4,8-dimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 6.96-6.75 (m, 2H), 6.62 (d, J=6.9 Hz, 1H),4.97 (t, J=5.3 Hz, 1H), 4.39 (d, J=6.6 Hz, 1H), 3.97 (t, J=2.7 Hz, 1H),3.70 (dd, J=11.8, 6.9 Hz, 2H), 3.17 (dd, J=5.2, 1.7 Hz, 1H), 2.99 (d,J=1.7 Hz, 3H), 2.47-2.22 (m, 4H), 2.08 (d, J=1.7 Hz, 3H).

Compound 674.(S)-7-(tert-butoxymethyl)-4,8-dimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.93 (s, 1H), 6.41 (dd, J=9.4, 5.6 Hz,2H), 5.04 (d, J=6.2 Hz, 1H), 4.75 (tt, J=7.4, 4.0 Hz, 1H), 4.55 (ddd,J=13.5, 6.7, 3.8 Hz, 1H), 4.09 (q, J=3.1 Hz, 1H), 3.71 (d, J=3.6 Hz,2H), 3.09 (s, 3H), 2.59 (ddt, J=15.3, 7.3, 3.4 Hz, 2H), 2.42 (dt,J=13.3, 6.3 Hz, 2H), 2.21 (d, J=2.9 Hz, 3H), 1.05 (d, J=3.3 Hz, 9H).

Compound 667.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 6.94-6.79 (m, 2H), 6.69 (d,J=6.8 Hz, 1H), 4.84 (td, J=6.6, 3.3 Hz, 1H), 4.39 (dd, J=13.2, 6.4 Hz,1H), 4.21 (s, 1H), 3.10 (s, 3H), 3.06 (d, J=4.5 Hz, 3H), 2.40 (dd,J=13.8, 9.7 Hz, 1H), 2.37-2.28 (m, 2H), 2.23 (dd, J=9.0, 3.5 Hz, 1H),2.18-2.05 (m, 5H), 1.98 (dd, J=18.6, 8.9 Hz, 1H), 1.70 (ddd, J=20.2,10.2, 4.7 Hz, 1H), 1.56 (dt, J=9.0, 7.9 Hz, 1H).

Compound 599.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((trans-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 6.48-6.24 (m, 2H), 5.11(d, J=6.1 Hz, 1H), 4.74 (tt, J=7.1, 4.0 Hz, 1H), 4.56 (td, J=8.1, 5.7Hz, 1H), 3.94 (d, J=6.1 Hz, 1H), 3.57 (p, J=6.3 Hz, 1H), 3.30 (s, 3H),3.18 (s, 3H), 2.59 (ddt, J=12.4, 8.4, 4.2 Hz, 2H), 2.51-2.39 (m, 2H),2.25 (s, 3H), 1.25 (dd, J=12.1, 4.0 Hz, 6H).

Example 2QQ General Scheme and Procedure for Preparation of Examples inTable 41

Procedure for the examples in Table 41 were prepared by the Method Aprocedure (see Compound 46) via reaction of Intermediates A-# and B-112.

TABLE 41 Comp. No. R₃ R₄ Int A [α]_(D) M + 1 748 -CH₃ H A-3 437.29 (R₁ =CH₃) 725 -CH₂OtBu H A-63 495.47 (R₁ = H) 669

H A-66 (R₁ = H) 119.1 c = 1.0 MeOH 507.27 685 -iPr H A-9 36.8 451.22 (R₁= H) c = 1.0 DMSO 684 -(R)- H A-59 40.0 467.28 CH(OCH₃)CH₃ (R₁ = H) c =1.0 DMSO 686 -CH₂CH₃ H A-8 23.8 437.21 (R₁ = H) c = 1.0 DMSO 724-CH₂OCH3 -CH3 A-69 52.4 467.3 (R₁ = H) c = 0.5 MeOH

Compound 748.(7S)-4,5,7,8-tetramethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J=2.7 Hz, 1H), 7.83 (d, J=8.8Hz, 1H), 7.61-7.50 (m, 1H), 5.21-5.10 (m, 1H), 4.76-4.61 (m, 1H),4.38-4.26 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H), 2.86-2.61 (m, 4H), 2.55(s, 3H), 1.39 (d, J=7.0 Hz, 3H).

Compound 725.(S)-7-(tert-butoxymethyl)-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.31 (d, J=3.0 Hz, 1H), 7.61 (d, J=8.6Hz, 1H), 7.17 (dd, J=8.8, 2.9 Hz, 1H), 5.20-5.00 (m, 1H), 4.95 (tt,J=7.0, 4.0 Hz, 1H), 4.59 (dd, J=12.0, 6.1 Hz, 1H), 4.09 (t, J=3.2 Hz,1H), 3.71 (d, J=3.4 Hz, 2H), 3.08 (d, J=4.2 Hz, 2H), 2.75-2.57 (m, 2H),2.57-2.36 (m, 3H), 2.21 (d, J=2.9 Hz, 3H), 1.05 (d, J=4.3 Hz, 9H).

Compound 669.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-((trans-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.82(d, J=8.7 Hz, 1H), 7.45 (dd, J=8.5, 2.7 Hz, 1H), 6.75 (s, 1H), 5.02 (s,1H), 4.52-4.37 (m, 1H), 4.22 (s, 1H), 3.10 (s, 3H), 3.06 (s, 3H),2.44-2.34 (m, 1H), 2.22 (d, J=3.8 Hz, 1H), 2.18-2.06 (m, 5H), 1.99 (d,J=9.4 Hz, 1H), 1.79-1.62 (m, 1H), 1.61-1.45 (m, 1H).

Compound 685.(S)-7-isopropyl-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.82(d, J=8.7 Hz, 1H), 7.45 (dd, J=8.5, 2.7 Hz, 1H), 6.75 (s, 1H), 5.02 (s,1H), 4.52-4.37 (m, 1H), 4.22 (s, 1H), 3.10 (s, 3H), 3.06 (s, 3H),2.44-2.34 (m, 1H), 2.22 (d, J=3.8 Hz, 1H), 2.18-2.06 (m, 5H), 1.99 (d,J=9.4 Hz, 1H), 1.79-1.62 (m, 1H), 1.61-1.45 (m, 1H).

Compound 684.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.31 (d, J=2.9 Hz, 1H), 7.75 (dd, J=8.9,2.1 Hz, 1H), 7.44 (dd, J=8.7, 2.9 Hz, 1H), 5.13-5.01 (m, 1H), 4.68 (q,J=7.0 Hz, 1H), 4.23 (dd, J=3.9, 2.0 Hz, 1H), 3.79 (qd, J=6.5, 3.9 Hz,1H), 3.32 (s, 3H), 3.29 (s, 3H), 2.70 (dq, J=7.4, 4.2 Hz, 4H), 2.33 (d,J=2.1 Hz, 3H), 1.29 (dd, J=6.5, 2.1 Hz, 3H)

Compound 686.(S)-7-ethyl-4,8-dimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d₄) δ 8.31 (d, J=2.7 Hz, 1H), 7.80-7.70 (m,1H), 7.44 (dd, J=8.7, 2.8 Hz, 1H), 5.09 (t, J=5.4 Hz, 1H), 4.72-4.60 (m,1H), 4.41-4.24 (m, 1H), 3.25 (s, 3H), 2.79-2.59 (m, 4H), 2.33 (d, J=1.5Hz, 3H), 2.15-1.84 (m, 2H), 0.93-0.79 (m, 3H).

Compound 724.7-(methoxymethyl)-4,7,8-trimethyl-2-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 7.83(d, J=8.7 Hz, 1H), 7.46 (dd, J=8.6, 2.8 Hz, 1H), 6.72 (s, 1H), 5.02 (s,1H), 4.53-4.24 (m, 1H), 3.66 (d, J=10.0 Hz, 1H), 3.54 (d, J=10.1 Hz,1H), 3.20 (s, 3H), 2.93 (d, J=31.5 Hz, 3H), 2.45-2.31 (m, 1H), 2.09 (d,J=7.1 Hz, 3H), 1.29 (d, J=36.9 Hz, 2H).

Example 2RR General Scheme and Procedure for Preparation of Examples inTable 42

The examples in Table 42 were prepared by the Method A procedure (seeCompound 46) via reaction of Intermediates A-# and B-115.

TABLE 42 Appl. R₃ = No. R₄ = Int A [α]_(D) M + 1 645 R₃ = Et A-8 19.8438.18 R₄ = H c = 1.0 DMSO 644 R₃ = iPr A-9 30.3 452.22 R₄ = H c = 1.0DMSO 657 R₃ = (R)- A-59 43.9 468.29 CH(OCH3)CH3 c = 1.0 R₄= H DMSO 718

A-66 96.8 c = 0.5 MeOH 494.31 710 R₃ = -CH₃ A-70 −31.5 468.25 R₄ = c =0.6 -CH₂OCH₃ MeOH 706 R₃ = A-69 45.8 468.25 -CH₂OCH₃ c = 0.7 R₄ = -CH₃MeOH

Compound 645.(S)-7-ethyl-4,8-dimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.55 (s, 2H), 5.17 (t, J=5.3 Hz, 1H),4.67 (t, J=7.2 Hz, 1H), 4.33 (dd, J=5.8, 3.4 Hz, 1H), 3.23 (s, 3H), 2.73(dp, J=7.3, 2.2 Hz, 4H), 2.32 (s, 3H), 2.13-1.93 (m, 2H), 0.86 (td,J=7.4, 2.9 Hz, 3H).

Compound 644.(S)-7-isopropyl-4,8-dimethyl-2-((cis-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d₄) δ 8.56 (s, 2H), 5.18 (td, J=6.0, 3.0 Hz,1H), 4.68 (q, J=7.1 Hz, 1H), 4.16 (d, J=3.8 Hz, 1H), 3.27 (s, 3H), 2.74(qd, J=7.0, 6.4, 2.3 Hz, 4H), 2.33 (s, 3H), 1.11 (d, J=7.0 Hz, 3H), 0.89(d, J=6.9 Hz, 3H)

Compound 657.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Chloroform-d) δ 9.75 (s, 2H), 8.40 (s, 2H), 6.84 (s,1H), 5.02 (tt, J=7.0, 3.8 Hz, 1H), 4.63 (ddt, J=14.0, 7.9, 6.0 Hz, 1H),3.96 (d, J=5.6 Hz, 1H), 3.68-3.56 (m, 1H), 3.29 (s, 3H), 3.21 (s, 3H),2.72-2.52 (m, 3H), 2.29 (s, 3H), 1.25 (d, J=6.4 Hz, 3H).

Compound 718.7-(1-methoxycyclobutyl)-4,8-dimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 2H), 8.66 (s, 4H), 6.74 (d, J=7.1Hz, 2H), 5.12 (d, J=6.9 Hz, 2H), 4.46 (d, J=7.2 Hz, 1H), 4.21 (s, 2H),3.10 (s, 6H), 2.28-2.18 (m, 2H), 3.06 (s, 6H), 2.10 (s, 11H), 1.98 (s,2H), 1.75-1.61 (m, 1H), 1.55 (d, J=9.4 Hz, 2H), 1.27-1.22 (m, 2H),1.21-1.10 (m, 4H).

Compound 710.7-(methoxymethyl)-4,7,8-trimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H), 8.66 (s, 2H), 6.75 (s, 1H),5.21-5.04 (m, 1H), 4.45 (q, J=7.2 Hz, 1H), 3.66 (d, J=10.0 Hz, 1H), 3.55(d, J=10.1 Hz, 1H), 3.20 (s, 3H), 2.97 (s, 3H), 2.11 (s, 3H), 1.33 (s,3H).

Compound 706.7-(methoxymethyl)-4,7,8-trimethyl-2-((trans-3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 7.67 (s, 1H), 7.40 (s, 1H),6.58 (s, 1H), 6.48 (s, 1H), 5.44 (s, 2H), 4.21 (d, J=6.1 Hz, 2H), 3.87(s, 3H), 3.65 (d, J=10.0 Hz, 1H), 3.54 (d, J=10.1 Hz, 1H), 3.19 (s, 3H),2.96 (s, 3H), 2.10 (s, 3H), 1.32 (s, 3H).

Example 2SS

The following compounds in Table 43 were prepared by reaction ofIntermediates A-9 and Intermediate B-# via Method A procedure.

TABLE 43 Inter- Compound # Ring Q2 mediate B [α]_(D) M + 1 Compound 502

B-204 34.9 c = 1.0 MeOH 477.38 Compound 503

B-205 −24.2 c = 1.0 MeOH 477.33 Compound 504

B-206 165.3 c = 1.0 MeOH 477.29 Compound 505

B-207 98.8 c = 1.0 MeOH 477.29

Compound 502.(S)-7-isopropyl-4,8-dimethyl-2-(((1S,3R)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.81 (s, 4H), 4.46 (dq, J=16.1, 8.1 Hz,2H), 4.15 (d, J=3.8 Hz, 1H), 3.34-3.28 (m, 2H), 3.26 (s, 3H), 2.50 (d,J=18.8 Hz, 1H), 2.43-2.33 (m, 1H), 2.32 (d, J=5.2 Hz, 3H), 2.23-1.89 (m,5H), 1.10 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H).

Compound 503.(S)-7-isopropyl-4,8-dimethyl-2-(((1S,3S)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.99 (t, J=15.0 Hz, 2H), 7.92 (d, J=8.7Hz, 2H), 4.72-4.53 (m, 2H), 4.15 (d, J=3.8 Hz, 1H), 33.32 (s, 3H), 3.30(s, 3H), 2.56-2.32 (m, 3H), 2.31 (d, J=5.8 Hz, 3H), 2.22-2.00 (m, 2H),1.77 (ddt, J=13.0, 10.1, 7.5 Hz, 1H), 1.10 (d, J=7.0 Hz, 3H), 0.88 (d,J=6.9 Hz, 3H).

Compound 504.(S)-7-isopropyl-4,8-dimethyl-2-(((1R,3R)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.78 (t, J=10.6 Hz, 4H), 4.68-4.54 (m,2H), 4.15 (d, J=3.8 Hz, 1H), 3.28 (d, J=8.2 Hz, 3H), 3.21 (s, 3H),2.45-2.33 (m, 2H), 2.31 (s, 3H), 2.15 (d, J=7.7 Hz, 1H), 2.08-1.87 (m,2H), 1.78 (ddt, J=13.1, 10.0, 7.5 Hz, 1H), 1.11 (d, J=7.0 Hz, 3H), 0.89(d, J=6.9 Hz, 3H).

Compound 505.(S)-7-isopropyl-4,8-dimethyl-2-(((1R,3S)-3-(methyl(4-(trifluoromethyl)phenyl)amino)cyclopentyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (400 MHz, Methanol-d4) δ 7.82 (s, 4H), 4.53-4.35 (m, 2H), 4.15(d, J=3.8 Hz, 1H), 3.26 (d, J=4.3 Hz, 6H), 2.49 (d, J=14.7 Hz, 1H),2.24-1.90 (m, 5H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H)

Example 2TT

The following compounds of Table 44 were prepared by reaction ofIntermediates A-67 and Intermediate B-# via Method A procedure.

TABLE 44 Intermediate Comp. No. Q₂-L₂-Ring B B M + 1 687

B-209 465.32 688

B-210 452.22 689

B-112 465.54 697

B-195 479.27

Compound 687.4′,8′-dimethyl-2′-((cis-3-((5-(trifluoromethyl)pyrazin-2-yl)amino)cyclobutyl)amino)-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

¹H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.89 (d, J=1.4 Hz, 1H),7.78 (s, 1H), 5.19 (d, J=6.9 Hz, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.33-4.24(m, 2H), 4.22-4.13 (m, 3H), 3.91 (q, J=8.6 Hz, 1H), 3.14 (s, 4H), 3.04(dtd, J=9.8, 7.2, 2.9 Hz, 2H), 2.62 (ddd, J=13.5, 7.7, 3.5 Hz, 1H), 2.22(s, 3H), 1.85 (qd, J=8.8, 2.8 Hz, 2H).

Compound 688.4′,8′-dimethyl-2′-((trans-3-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)cyclobutyl)amino)-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

¹H NMR (400 MHz, Methanol-d4) δ 7.75 (dd, J=2.3, 1.0 Hz, 1H), 6.58 (d,J=2.3 Hz, 1H), 4.30-4.24 (m, 4H), 4.22-4.14 (m, 2H), 3.87-3.76 (m, 1H),3.25 (d, J=1.2 Hz, 3H), 2.66-2.59 (m, 1H), 2.56-2.49 (m, 2H), 2.30 (s,3H), 1.88 (qd, J=8.9, 2.6 Hz, 2H).

Compound 689.4′,8′-dimethyl-2′-((trans-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)cyclobutyl)amino)-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J=2.8 Hz, 1H), 7.75 (d, J=8.7Hz, 1H), 7.43 (dd, J=8.7, 2.8 Hz, 1H), 5.07 (t, J=5.2 Hz, 1H), 4.64 (t,J=7.2 Hz, 1H), 4.30-4.12 (m, 4H), 3.83 (td, J=9.3, 7.3 Hz, 1H), 3.25 (s,3H), 2.68 (dd, J=7.2, 5.2 Hz, 4H), 2.62-2.58 (m, OH), 2.46-2.36 (m, 1H),2.32 (s, 3H).

Compound 697.4′,8′-dimethyl-2′-((cis-3-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)cyclobutyl)amino)-4,5,5′,8′-tetrahydro-2H,6′H-spiro[furan-3,7′-pteridin]-6′-one

¹H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J=2.8 Hz, 1H), 7.75 (d, J=8.7Hz, 1H), 7.55 (dd, J=8.8, 2.8 Hz, 1H), 4.41 (t, J=8.2 Hz, 1H), 4.26 (q,J=3.8, 2.7 Hz, 1H), 4.20-4.14 (m, 3H), 3.84 (td, J=9.2, 7.3 Hz, 1H),3.28 (s, 3H), 2.67-2.58 (m, 4H), 2.45-2.37 (m, 1H), 2.32 (s, 3H), 2.04(qd, J=7.9, 7.4, 3.8 Hz, 2H).

Example 2UU

Compound 506 and 507.(7S)-4,7,8-trimethyl-2-(((trans)-3-(4-(trifluoromethoxy)phenyl)cyclo-butyl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((cis)-3-(4-(trifluoromethoxy)phenyl)cyclo-butyl)amino)-7,8-dihydropteridin-6(5H)-one

Compound 503 and Compound 504 were prepared by reaction of IntermediateA-2 (220 mg, 0.975 mmol) and3-(4-(trifluoromethoxy)phenyl)cyclobutan-1-amine hydrochloride (261 mg,0.975 mmol) by the Method B procedure (see Compound 1) that provided amixture of the cis:trans isomers. The isomers were separated by SFC(OJ-H column, 20×250 mm; 20% methanol (5 mM ammonia)/80% CO2, Isocratic;80 ml/min): Peak A Rt 0.506 mins and Peak B (cis) Rt 0.653 mins.

Compound 506: Peak A (trans isomer), 37 mg; 1H NMR (400 MHz, CDCl3) δ8.33 (s, 1H), 7.38-7.31 (m, 2H), 7.21 (t, J=10.7 Hz, 2H), 5.04 (d, J=6.3Hz, 1H), 4.58-4.43 (m, 1H), 4.09 (q, J=6.9 Hz, 1H), 3.73-3.58 (m, 1H),3.06 (d, J=5.2 Hz, 3H), 2.59 (dddd, J=10.9, 7.8, 6.1, 3.2 Hz, 2H),2.50-2.35 (m, 2H), 2.24 (s, 3H), 1.41 (d, J=6.9 Hz, 3H). ESI-MS m/zcalc. 421.17255, found 422.28 (M+1)⁺;

Compound 507: Peak B (cis isomer), 89 mg; 1H NMR (400 MHz, CDCl3) δ 9.34(s, 1H), 7.24 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 5.48 (s, 1H),4.51-4.31 (m, 1H), 4.09 (q, J=6.8 Hz, 1H), 3.33-3.17 (m, 1H), 3.08 (s,3H), 2.96-2.76 (m, 2H), 2.29 (s, 3H), 2.01 (td, J=11.7, 2.5 Hz, 2H),1.43 (d, J=6.9 Hz, 3H). ESI-MS m/z calc. 421.17255, found 422.28 (M+1)⁺

Example 2VV

Compound 673.(7S)-7-isopropyl-4,8-dimethyl-2-((trans-3-(5-(trifluoromethyl)-1H-pyrazol-1-yl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by Method A (Compound 46) procedure byreaction of Intermediates A-9 and B-197a to provide the title product.1H NMR (400 MHz, Chloroform-d) δ 8.43 (s, 1H), 7.43 (q, J=1.1 Hz, 1H),6.46 (d, J=2.3 Hz, 1H), 4.99-4.77 (m, 2H), 4.51 (tt, J=8.5, 4.7 Hz, 1H),3.81 (dd, J=4.4, 1.6 Hz, 1H), 3.03 (d, J=1.1 Hz, 3H), 2.96-2.81 (m, 2H),2.50 (ddd, J=13.4, 8.6, 4.9 Hz, 2H), 2.19-2.13 (m, 1H), 2.13 (t, J=1.4Hz, 3H), 1.04-0.91 (m, 3H), 0.84 (d, J=6.9 Hz, 3H). ESI-MS m/z calc.423.19943, found 424.3 (M+1)⁺; [α]=67.3° (c=1.0, DMSO).

Example 2WW

The following compounds were prepared by the same procedure describedfor Compound 409 via the same scheme:

Compound 567 (R═CF3).(7S)-7-cyclobutyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.83 (s, 1H), 7.75-7.62(m, 2H), 7.57 (d, J=0.7 Hz, 1H), 7.44 (d, J=0.7 Hz, 1H), 5.37 (s, 2H),4.87 (d, J=5.9 Hz, 1H), 4.57-4.35 (m, 2H), 3.86 (d, J=7.9 Hz, 1H), 3.09(s, 3H), 2.67 (h, J=8.0 Hz, 1H), 2.21 (s, 3H), 2.05 (qd, J=8.9, 3.3 Hz,3H), 1.99-1.60 (m, 3H). ESI-MS m/z 487.23 (M+1)⁺; Chiral HPLC (ChiralPAKIC Column; Method: 20% methanol/30% ethanol/50% hexanes): Rt (95% ee);[α]=62.4° (c=1.0, CHCl₃)@22.7° C.

Compound 566 (R═Cl).(7S)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-cyclobutyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, Chloroform-d) δ 8.30 (d, J=2.5 Hz, 1H), 7.55 (s, 1H),7.51 (dd, J=8.5, 2.9 Hz, 2H), 7.39 (s, 1H), 7.33 (s, OH), 5.27 (s, 2H),4.85 (s, 1H), 4.43 (d, J=5.8 Hz, 2H), 3.87 (d, J=7.9 Hz, 1H), 3.09 (s,3H), 2.65 (p, J=8.3 Hz, 1H), 2.20 (s, 3H), 2.14-1.99 (m, 3H), 1.99-1.74(m, 3H). ESI-MS m/z 453.41 (M+1)⁺; Chiral HPLC (ChiralPAK IC Column;Method: 20% methanol/30% ethanol/50% hexanes): Rt (98% ee); [α]=133.76°(c=1.0, CHCl₃)@22.7° C.

Compound 660 (R₃=iPr).(S)-7-isopropyl-4,8-dimethyl-2-(((1s,3R)-3-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by Method B (Compound 1) procedure by reactionof A-9 and B-173 to provide the title product. 1H NMR (400 MHz,Methanol-d4) δ 4.38 (p, J=8.2 Hz, 1H), 4.14 (d, J=3.8 Hz, 1H), 3.27 (s,3H), 3.22 (d, J=7.2 Hz, 2H), 2.79-2.64 (m, 2H), 2.64-2.54 (m, 1H), 2.34(dt, J=6.9, 3.5 Hz, OH), 2.30 (s, 3H), 1.93 (dtd, J=10.9, 9.0, 5.9 Hz,2H), 1.11 (d, J=7.0 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H); ESI-MS m/z calc.439.19437, found 440.33.

Compound 664 (R₃=—(R)—CH(OCH₃)CH₃.(S)-7-((R)-1-methoxyethyl)-4,8-dimethyl-2-(((1s,3R)-3-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by Method B (Compound 1) procedure by reactionof A-59 and B-173 to provide the title product. 1H NMR (400 MHz,Methanol-d4) δ 4.40 (q, J=8.2 Hz, 1H), 4.23 (d, J=3.8 Hz, 1H), 3.79 (qd,J=6.4, 3.7 Hz, 1H), 3.34 (s, 3H), 3.29 (s, 3H), 3.23 (d, J=7.3 Hz, 2H),2.71 (tt, J=7.5, 3.8 Hz, 2H), 2.60 (dt, J=9.3, 7.4 Hz, 1H), 2.32 (s,3H), 2.01-1.90 (m, 2H), 1.28 (d, J=6.5 Hz, 3H). ESI-MS m/z calc.455.18927, found 456.27. [α]=36.0° (c=1.0, DMSO)@23° C.

Compound 428.(S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-imidazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

The compound was prepared by Method A (Compound 46) procedure byreaction of Intermediates A-1 and B-180 to provide the title product. 1HNMR (300 MHz, Methanol-d4) δ 8.57 (s, 1H), 8.44 (s, 1H), 7.75 (dd,J=12.1, 7.0 Hz, 2H), 7.43 (s, 1H), 7.32 (d, J=15.5 Hz, OH), 5.61 (d,J=28.3 Hz, 2H), 4.65 (q, J=16.0 Hz, 1H), 4.25 (d, J=6.9 Hz, 1H), 4.12(s, 1H), 3.09 (d, J=18.5 Hz, 3H), 2.20 (d, J=22.5 Hz, 3H), 1.43 (dd,J=40.0, 6.9 Hz, 3H); ESI-MS m/z 447.29.

Compound 413.(7S)-2-(((1-((2-acetyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

Mixture of1-(3-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)ethan-1-onehydrochloride (814 mg, 2.432 mmol),(7S)-2-chloro-4,7,8-trimethyl-5,7-dihydropteridin-6-one (500 mg, 2.206mmol) and NaOtBu (742.0 mg, 7.721 mmol) was taken into t-butanol (10 mL)and heated to 35° C. The reaction was purged by bubbling nitrogen for 30mins. tBuXPhosPd palladcycle (Gen 1; 31 mg, 0.04514 mmol) was added thereaction. The reaction was purged with nitrogen for 5 mins. then heatedat 50° C. for 45 minutes. The t-butanol was removed in vacuo and theresidues was dissolved dichloromethane (20 ml) plus some methanol andfiltered through celite. The filtrate was evaporated in vacuo and theresidue purified by column chromatography (SiO2; 40 g) eluting with agradient of dichloromethane to 20% methanol in dichloromethane. Thedesired fractions were evaporated in vacuo to afford the the product(500 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 7.78-7.67 (m, 2H), 7.60(s, 1H), 7.54 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 5.77 (s, 2H), 4.88 (t,J=5.5 Hz, 1H), 4.56-4.39 (m, 2H), 4.10 (q, J=6.8 Hz, 1H), 3.07 (s, 3H),2.80 (s, 3H), 2.23 (s, 3H), 1.42 (d, J=6.9 Hz, 3H). ESI-MS m/z 489.14(M+1; [α]D=+43.71°, 9.7 mg in 1 mL of MeOH, temp=20.6° C.

Compound 419 & Compound 420.(7S)-2-(((1-((2-((S)-1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-oneand(7S)-2-(((1-((2-((R)-1-hydroxyethyl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-(((1-((2-acetyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(310 mg, 0.6219 mmol) was dissolved in methanol (10 ml) and cooled to 0°C. Sodium borohydride (25 mg, 0.6608 mmol) was added and warmed to roomtemperature over 2 hours. The reaction was evaporated in vacuo to afforda residue that was dissolved in to water and extracted withdichloromethane (2×25 ml). The extracts were combined, dried overanhydrous sodium sulfate, filtered, and evaporated in vacuo to affordthe crude product. The crude was purified by column chromatography(SiO2; 12 g) eluting with a gradient of dichloromethane to 20% methanol.The desired fractions were combined and evaporated in vacuo to provide230 mg desired product as a mixture of enantiomers. The enantiomers wereseparated by SFC (AD-H column; 20% isopropanol/80% CO2 (5 mM ammonia),isocratic) to provide enantiomers A and B.

Enantiomer A: 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.57 (t, J=4.0 Hz,2H), 7.48-7.35 (m, 2H), 5.42 (s, 2H), 5.14 (q, J=6.4 Hz, 1H), 4.90 (t,J=5.7 Hz, 1H), 4.55-4.35 (m, 2H), 4.09 (q, J=6.9 Hz, 1H), 3.05 (s, 3H),2.22 (s, 3H), 1.50-1.32 (m, 6H), 1.23 (d, J=6.1 Hz, 1H). ESI-MS m/z491.26 (M+1); [α]_(D)=48.3°, 10 mg in 1 mL of MeOH, temp=19.5° C.

Enantiomer B: 1H NMR (300 MHz, CDCl3) δ 7.63 (s, 1H), 7.58 (t, J=4.0 Hz,2H), 7.42 (d, J=7.1 Hz, 2H), 5.42 (s, 2H), 5.14 (q, J=6.5 Hz, 1H), 4.93(s, 1H), 4.52-4.35 (m, 2H), 4.09 (q, J=6.9 Hz, 1H), 3.05 (s, 3H), 2.22(s, 3H), 1.43 (dd, J=8.9, 6.7 Hz, 6H). ESI-MS m/z 491.26 (M+1)⁺;[α]_(D)=37.38°, 10 mg in 1 mL of MeOH, temp=21.2° C.

Compound 416.(7S)-2-(((1-((2-(2-hydroxypropan-2-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

(7S)-2-(((1-((2-acetyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(184 mg, 0.3692 mmol) was dissolved in THF (5 mL) and cooled to −78° C.under N2. Methyl magnesium chloride (400 μL of 3 M, 1.200 mmol) wasadded to the solution dropwise. After the addition, the reaction waswarmed to room temperature over 2 hours. The reaction was quenched bythe addition of an ammonium chloride solution then extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate,filtered, and evaporated in vacuo. The crude product was purified bycolumn chromatography (SiO2; 12 g) eluting with a gradient ofdichloromethane to 20% methanol. The desired fractions were combined andevaporated to afford the desired product (102 mg, 46% yield). 1H NMR(300 MHz, DMSO) δ 12.64 (s, 1H), 10.50 (s, 1H), 8.03-7.82 (m, 2H), 7.70(d, J=8.1 Hz, 1H), 7.54 (s, 1H), 7.15 (d, J=8.0 Hz, 1H), 5.85 (s, 2H),4.43 (d, J=5.7 Hz, 2H), 4.31 (q, J=6.8 Hz, 1H), 3.21-3.07 (m, 4H), 2.26(s, 3H), 1.56 (s, 6H), 1.41 (d, J=6.9 Hz, 3H). ESI-MS m/z 505.3 (M+1);[α]_(D)=+13.2°, c=1.0, MeOH.

Compound 412.(S)-2-(((3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

The compound was prepared by Method B (Compound 1) procedure by reactionof Intermediates A-1 and B-164 to provide the title product. 1H NMR (300MHz, Chloroform-d) δ 8.89 (s, 1H), 8.66-8.49 (m, 1H), 7.87-7.55 (m, 2H),7.38 (s, 1H), 5.29 (s, 2H), 5.03 (t, J=6.0 Hz, 1H), 4.51-4.20 (m, 2H),4.04 (q, J=6.8 Hz, 1H), 3.01 (s, 3H), 2.23 (s, 3H), 1.38 (d, J=6.8 Hz,3H). ESI-MS m/z calc. 524.08954, found 525.36 (M+1)⁺. Chiral HPLC(ChiralPAK IC column; 20% methanol/30% ethanol/50% hexanes) Rt 6.241mins. (98% ee). [α]_(D)=+13.2° C.=0.585, CHCl3.

Example 2XX Synthesis of the Radioligand Used in the WFS1 BindingDisplacement Assay(7S)-4,7,8-trimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl-3-tritio)methyl)amino)-7,8-dihydropteridin-6(5H)-one

10% Palladium on Carbon (1.0 mg) was added to a Tritium reaction vessel,followed by a solution of(S)-2-(((3-bromo-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one(1.0 mg) in DMF (0.3 mL) and DIEA (0.1 ml). The vessel was attached tothe Tritium line and pressurized to 0.5 atm with Tritium gas at −200° C.The solution was stirred for 1 hour at room temperature, cooled to −200°C. and excess gas removed. The reaction flask was rinsed with 4×5 mLCH3OH passing each of the methanol washes through a celite pad. Thecombined methanol washes was removed under vacuum. Crude yield: 30 mCi.The material was purified by semi-prep reverse phase HPLC. Mobile phasewas removed under vacuum and the product was re-dissolved in absoluteEthanol. Yield: 15 mCi, purity>99%. The Specific Activity was determinedto be 19.9 Ciimmol by Mass Spec.

Example 2YY

Step 1: 2-((Dimethylamino)methylene)cyclopentane-1,3-dione

Cyclopentane-1,3-dione (10 g, 101.9 mmol) and1,1-dimethoxy-N,N-dimethyl-methanamine (16 g, 134.3 mmol) were takeninto dichloromethane (90 mL) and stirred at room temperature for hr. Thereaction was evaporated in vacuo and the residue was triturated withcyclohexane (2×25 mL) to afford a pale yellow solid of the desiredproduct (18 g)¹H NMR (300 MHz, Chloroform-d) δ 7.44 (s, 1H), 3.72 (s,3H), 3.36 (s, 3H), 2.50 (s, 4H). ESI-MS m/z calc. 153.07898, found154.11 (M+1).

Step 2: 2-(((Tosylmethyl)amino)methylene)cyclopentane-1,3-dione

2-((Dimethylamino)methylene)cyclopentane-1,3-dione (18 g, 110%) and4-methylbenzenesulfonohydrazide (19.93 g, 107.0 mmol) were taken intomethanol and stirred at room temperature for 1 hr. The reaction wasevaporated in vacuo to provide the desired product as a yellow solidthat was washed with hexanes and filtered to provide the desired product(25.5 g, 82%). ¹H NMR (300 MHz, Chloroform-d) δ 7.86-7.80 (m, 1H),7.80-7.75 (m, 1H), 7.38 (d, J=8.1 Hz, 1H), 7.29 (d, J=2.7 Hz, 2H), 2.73(s, 3H), 2.47 (s, 1H), 2.40 (s, 3H). ESI-MS m/z calc. 294.0674, found295.12 (M+1)⁺.

Step 3: 5,6-Dihydrocyclopenta[c]pyrazol-4(1H)-one

A mixture of 2-(((Tosylmethyl)amino)methylene)cyclopentane-1,3-dione (5g, 2 mmol), HCl (20 mL, 37% aqueous) and n-BuOH (40 mL) was stirred at110° C. for 12 h. The black reaction mixture was concentrated in vacuoto afford the dark crude product which was purified by MPLC (SiO2; 40 g)eluting with a gradient of 0-10% methanol in dichloromethane. Therelevant fractions were combined and evaporated in vacuo to afford theproduct as a yellow solid (1.2 g, 48%). ¹H NMR (300 MHz, Chloroform-d) δ7.78 (s, 1H), 3.06 (d, J=0.9 Hz, 4H). ESI-MS m/z calc. 122.04801, found123.06 (M+1)⁺.

Step 4:1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-5,6-dihydrocyclopenta[c]pyrazol-4(1H)-one& 2-((6-(Trifluoromethylpaladl)pyridin-3-yl)methyl)-5,6-dihydrocyclopenta[c]pyrazol-4(2H)-one

5,6-Dihydrocyclopenta[c]pyrazol-4(1H)-one (1.15 g, 9.357 mmol),5-(chloromethyl)-2-(trifluoromethyl)pyridine (2.1 g, 10.74 mmol), andK₂CO₃ (2.5 g, 31.2 mmol) were taken into acetonitrile (20 mL). Themixture was heated to reflux for 3 hours. After cooling to roomtemperature, the reaction mixture was diluted with water (40 m L) andextracted with ethyl acetate (3×15 ml). The combined organic extractswere dried over magnesium sulfate, filtered, and evaporated in vacuo.The crude product was purified by column chromatography (SiO₂) elutingwith a gradient of 0-10% methanol in dichloromethane. The relevantfractions were combined and evaporated in vacuo to provide the titleproduct (as a mixture of regioisomers) as a yellow crystalline solid(2.56 g, 96%). ¹H NMR (300 MHz, Chloroform-d) δ 8.71 (d, J=2.1 Hz, 1H),7.86-7.75 (m, 2H), 7.71 (dd, J=8.2, 0.9 Hz, 1H), 5.45 (s, 2H), 3.10-3.01(m, 2H), 3.00-2.93 (m, 2H). ESI-MS m/z calc. 281.0776, found 282.2(M+1)⁺.

Step 5:1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-ol&2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-ol

The mixture of regioisomers from Step 4 (1 g, 3.556 mmol) was dissolvedin methanol. Sodium borohydride (134.5 mg, 142.3 μL, 3.556 mmol) wasadded to the solution and stirred at room temperature for 1 hr. Thereaction was evaporated in vacuo. The residue was dissolved indichloromethane and washed with water. The organic layer was dried oversodium sulfate, filtered, and evaporated in vacuo. The crude product waspurified by column chromatography (SiO2; 40 g) eluting with a gradientof 0-100% ethyl acetate in hexanes followed by 2-5% methanol indichloromethane. The relevant fractions were combined and evaporated toprovide the title product (as a mixture of regioisomers) as a lightbrown solid (0.76 g, 75%). The ¹H NMR showed two isomers, but LCMS onlyshowed one peak. ¹H NMR (300 MHz, Chloroform-d) δ 8.51 (dd, J=5.0, 2.0Hz, 1H), 7.64 (ddd, J=6.3, 4.3, 2.3 Hz, 1H), 7.57 (dt, J=8.2, 1.1 Hz,1H), 7.27 (d, J=19.8 Hz, 1H), 5.23 (d, J=18.0 Hz, 2H), 5.16-4.99 (m,1H), 2.85 (dddd, J=13.7, 10.8, 5.9, 2.0 Hz, 1H), 2.79-2.64 (m, 1H),2.63-2.40 (m, 1H), 2.40-2.18 (m, 1H), 2.17-2.00 (m, 1H). ESI-MS m/zcalc. 283.09326, found 284.13 (M+1)⁺; Retention time: 0.66 minutes.

Step 6:4-azido-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole&4-azido-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole

The product from Step 5 (0.76 g, 2.683 mmol) was taken into THE (10 ml)and cooled to 0° C. DBU (490 μL, 3.277 mmol) and DPPA (886.1 mg, 693.9μL, 3.220 mmol) were added to the solution and stirred at roomtemperature for 3 hours. The reaction was evaporated in vacuo. Theresulting residue was dissolved in dichloromethane and washed withwater. The organic layer was dried over Na₂SO₄ and concentrated to givethe crude product which was purified by column chromatography (SiO2; 12g) eluting with a gradient of 0-8% methanol in dichloromethane. Therelevant fractions were combined and evaporated in vacuo to give thedesired product (as a mixture of regioisomers) as clear light yellowliquid (650 mg, 78%). The ¹H NMR shows a mixture of regioisomers. 1H NMR(300 MHz, Chloroform-d) δ 8.73-8.58 (m, 1H), 7.80-7.64 (m, 2H), 7.44 (d,J=21.8 Hz, 1H), 5.37 (d, J=18.6 Hz, 2H), 4.81 (ddd, J=17.4, 6.6, 2.6 Hz,1H), 3.05-2.89 (m, 1H), 2.89-2.39 (m, 3H). ESI-MS m/z calc. 308.09973,found 309.13 (M+1)⁺; Retention time: 0.83 minutes

Step 7:1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-amine&2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-amine

Water (1 ml, 55.5 mmol) was added to a solution of the two regioisomersfrom Step 6(4-azido-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole&4-azido-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazole)(0.650 g, 2.11 mmol) and triphenylphosphine (0.98 g, 3.736 mmol) in THE(10 ml). The reaction was stirred at room temperature for 16 hours. Thereaction was evaporated in vacuo. The residue was dissolved in 2N HCl (5ml) and washed with ethyl acetate (2×10 mL). The aqueous layer wasbasified with 2N sodium hydroxide and extracted with dichloromethane(3×5 ml). The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and evaporated to provide the product as a mixture ofregioisomers as a light yellow oil (591 mg, 99%). ¹H NMR (300 MHz,Chloroform-d) δ 8.62 (d, J=2.9 Hz, 1H), 7.79-7.60 (m, 2H), 7.36 (s, 1H),7.24 (s, OH), 5.32 (d, J=16.5 Hz, 2H), 4.46-4.27 (m, 1H), 3.06-2.44 (m,3H), 2.30-1.96 (m, 1H). ESI-MS m/z calc. 282.10922, found 282.92 (M+1)⁺.

Step 8

The following final products were prepared to give Compound 519, 520,521, 522. These compounds were prepared by reaction of(7S)-2-chloro-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one (A-3;250 mg, 0.9815 mmol) and the mixture of the regioisomers from Step 7(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-amine&2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-amine(305 mg, 1.081 mmol) via the Method A procedure to afford the product asa mixture of enantiomers of each regioisomer (130 mg, 26%)

Chiral HPLC showed four peaks: R & S enantiomers of each regioisomer andeach isomer with R, S enantiomers. Chiral HPLC (Chiral PAK IC column;method 20% methanol/30% ethanol/50% hexanes, isocratic; in 25 mins.).The four isomers were separated by SFC chromatography (IA column, 10×250mm; 30% Ethanol (5 mM Ammonia)/70% CO2, isocratic, 15 ml/min) Peaks Aand B are pairs of diastereomers of the one regioisomer. Peaks C and Dare another pair of diastereomers of the other regioisomer. This wasdetermined by 1H NMR based on the proton shift of the pyrazole: higherfield proton shift (7.2 ppm) for the peaks A and B; lower field pyrazoleproton shift (7.4 ppm) for peaks C & D.

Compound 519 (Isomer A) and Compound 520 (Isomer B)(S)-7-isopropyl-4,8-dimethyl-2-(((S)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(S)-7-isopropyl-4,8-dimethyl-2-(((R)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneCompound 519 (Isomer A)

Isomer A (26 mg, 20%) 1H NMR (300 MHz, Chloroform-d) δ 8.69 (s, 1H),8.52 (d, J=2.0 Hz, 1H), 7.72-7.52 (m, 2H), 7.15 (s, 1H), 5.25 (s, 2H),5.22 (d, J=6.8 Hz, 3H), 3.81 (d, J=4.4 Hz, 1H), 3.04 (s, 3H), 2.81 (ddt,J=14.9, 8.1, 3.7 Hz, 2H), 2.64 (ddd, J=15.0, 9.4, 5.9 Hz, 1H), 2.27-2.03(m, 6H), 0.99 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.9 Hz, 3H), 0.83-0.59 (m,4H). ESI-MS m/z calc. 500.22598, found 501.54 (M+1)⁺.

Chiral HPLC (Chiral PAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic, 25 mins): Rt 6.934 mins (98% ee); [α]=28.5° (c=0.5,CHCl3)@22.2° C.

Compound 520 (Isomer B)

Isomer B (28.5 mg, 22%) 1H NMR (300 MHz, Chloroform-d) δ 8.99 (s, 1H),8.59 (s, 1H), 7.68 (q, J=8.3 Hz, 2H), 7.24 (s, 1H), 5.62 (s, 1H), 5.32(d, J=10.2 Hz, 3H), 3.91 (d, J=4.3 Hz, 1H), 3.14 (s, 3H), 2.91 (tdd,J=12.5, 8.7, 4.9 Hz, 2H), 2.73 (dt, J=14.9, 8.5 Hz, 1H), 2.40-2.07 (m,5H), 1.27 (s, 1H), 1.21 (dd, J=6.1, 4.0 Hz, 1H), 1.08 (d, J=6.9 Hz, 7H),0.94 (d, J=6.9 Hz, 3H). ESI-MS m/z calc. 500.22598, found 501.36 (M+1)⁺.Chiral HPLC (Chiral PAK IC column; 20% methanol/30% ethanol/50% hexanes,isocratic, 25 mins): Rt 6.45 mins (98% ee); [α]=135.1° (c=0.5,CHCl3)@22.2° C.

Compound 521 (Isomer C) and Compound 522(Isomer D)(S)-7-isopropyl-4,8-dimethyl-2-(((S)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(S)-7-isopropyl-4,8-dimethyl-2-(((R)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneCompound 521 (Isomer C)

Isomer C(7S)-7-isopropyl-4,8-dimethyl-2-[[2-[[6-(trifluoromethyl)-3-pyridyl]methyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]amino]-5,7-dihydropteridin-6-one(24.5 mg, 19%) 1H NMR (300 MHz, Chloroform-d) δ 8.78 (s, 1H), 8.59 (s,1H), 7.88-7.58 (m, 2H), 7.34 (s, 1H), 5.44 (s, 1H), 5.29 (s, 2H), 5.26(s, 1H), 4.34-4.09 (m, 1H), 3.89 (d, J=4.4 Hz, 1H), 3.14 (s, 3H), 3.01(p, J=7.3, 6.7 Hz, 1H), 2.75 (ddd, J=14.5, 8.4, 5.1 Hz, 1H), 2.55 (ddd,J=14.8, 8.6, 4.7 Hz, 1H), 2.41 (tt, J=8.9, 4.0 Hz, 1H), 2.23 (s, 4H),1.07 (d, J=6.9 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H). ESI-MS m/z calc.500.22598, found 501.27 (M+1)⁺; Chiral HPLC (Chiral PAK IC column; 20%methanol/30% ethanol/50% hexanes, isocratic, 25 mins): Rt 7.436 mins(98% ee); [α]=31° (c=0.5, CHCl3)@22.2° C.

Compound 522 (Isomer D)

Isomer D(7S)-7-isopropyl-4,8-dimethyl-2-[[2-[[6-(trifluoromethyl)-3-pyridyl]methyl]-5,6-dihydro-4H-cyclopenta[c]pyrazol-4-yl]amino]-5,7-dihydropteridin-6-one(31 mg, 24%) 1H NMR (300 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.58 (s,1H), 7.81-7.57 (m, 2H), 7.31 (s, 1H), 5.39-5.22 (m, 5H), 4.32-4.11 (m,1H), 3.87 (d, J=4.4 Hz, 1H), 3.12 (s, 3H), 3.03 (qd, J=8.3, 5.1 Hz, 1H),2.74 (ddd, J=14.2, 8.7, 4.9 Hz, 1H), 2.55 (ddd, J=14.9, 8.7, 5.0 Hz,1H), 2.39 (ddt, J=13.7, 9.2, 4.7 Hz, 1H), 2.21 (s, 4H), 1.17 (d, J=6.1Hz, 3H), 1.05 (d, J=6.9 Hz, 3H). ESI-MS m/z calc. 500.22598, found501.27 (M+1)⁺; Chiral HPLC (Chiral PAK IC column; 20% methanol/30%ethanol/50% hexanes, isocratic, 25 mins): Rt 7.407 mins (98% ee);[α]=114.1° (c=0.5, CHCl3)@22.2° C.

Example 2ZZ

Compounds 546, 547, 624, and 625

These compounds were prepared by reaction of A-2 (390 mg, 1.72 mmol) anda mixture of regioisomers(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-amine&2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-amine(585 mg, 2.073 mmol) via the Method A procedure reported for Compound46.

The product was a mixture of 2 regioisomers each as a pair ofdiastereomers. Chiral HPLC (Chiral PAK IC column; 20% methanol/30%ethanol/50% hexanes, isocratic, 25 mins).

The mixture was separated by SFC (IA column, 20×250 mm; 30% ethanol(0.2% diethylamine)/70% CO2, isocratic, 80 ml/min) to provide aninseparable mixture of Peaks A & B and clean separation of Peak C andPeak D. Peaks A & B were subjected to preparative chiral HPLC (ICcolumn, 20×250 mm; 70% hexanes/30% ethanol/methanol (0.2% diethylamine,Isocratic, 20 ml/min) to provide clean separation of Peak A and B.

Isomer A & B:(7S)-4,7,8-trimethyl-2-(((S)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((R)-1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneIsomer A; Compound 624

Isomer A: 1H NMR (300 MHz, Chloroform-d) δ 8.61 (d, J=1.9 Hz, 1H), 7.69(qd, J=8.8, 8.1, 2.2 Hz, 3H), 7.23 (s, 1H), 5.34 (s, 2H), 5.33-5.26 (m,1H), 4.88 (d, J=7.6 Hz, 1H), 4.10 (q, J=6.8 Hz, 1H), 3.06 (s, 3H),3.02-2.83 (m, 2H), 2.74 (ddd, J=15.2, 9.3, 6.1 Hz, 1H), 2.29 (dd, J=8.4,5.3 Hz, 1H), 2.22 (s, 3H), 1.42 (d, J=6.9 Hz, 3H). ESI-MS m/z calc.472.1947, found 473.12 (M+1). Chiral HPLC (AD-H column, 70% hexanes/15%methanol/15% ethanol (0.2% diethylamine)): Rt 6.754 mins. (98% ee).

Isomer B; Compound 625

Isomer B: 1H NMR (300 MHz, Chloroform-d) δ 8.61 (s, 1H), 7.79-7.62 (m,3H), 7.23 (s, 1H), 5.33 (d, J=8.7 Hz, 3H), 4.88 (d, J=7.6 Hz, 1H), 4.09(q, J=6.8 Hz, 1H), 3.06 (s, 3H), 2.98-2.86 (m, 1H), 2.91-2.65 (m, 2H),2.34-2.16 (m, 1H), 2.23 (s, 3H), 1.42 (d, J=6.8 Hz, 3H). ESI-MS m/zcalc. 472.1947, found 473.07 (M+1)⁺. Chiral HPLC (AD-H column, 70%hexanes/15% methanol/15% ethanol (0.2% diethylamine)): Rt 7.103 mins(98% ee). Isomer C & D:(7S)-4,7,8-trimethyl-2-(((S)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-oneand(7S)-4,7,8-trimethyl-2-(((R)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-4-yl)amino)-7,8-dihydropteridin-6(5H)-one

Isomer C; Compound 546

Isomer C: 1H NMR (300 MHz, Chloroform-d) δ 9.31 (s, 1H), 8.52 (d, J=1.9Hz, 1H), 7.78-7.48 (m, 2H), 7.27 (s, 1H), 5.23 (s, 2H), 5.23-5.10 (m,2H), 4.96 (d, J=7.4 Hz, 1H), 3.99 (q, J=6.8 Hz, 1H), 2.98 (s, 4H), 2.67(ddd, J=14.1, 8.6, 5.0 Hz, 1H), 2.49 (ddd, J=15.4, 8.8, 5.0 Hz, 1H),2.31 (dq, J=9.1, 4.5 Hz, 1H), 2.18 (s, 3H), 1.32 (d, J=6.8 Hz, 3H).ESI-MS m/z calc. 472.1947, found 473.36 (M+1)⁺. Chiral HPLC(Chiral PAKIC column, 20% methanol/30% ethanol/50% hexanes; 20 mins, Isocratic): Rt9.265 mins (95% ee). [α]=14.8° (c=0.5), CHCl3@20.8° C.

Isomer D; Compound 547

Isomer D: 1H NMR (300 MHz, Chloroform-d) δ 9.21 (s, 1H), 8.52 (d, J=1.9Hz, 1H), 7.70-7.52 (m, 2H), 7.25 (s, 1H), 5.23 (s, 2H), 5.18 (dt, J=7.4,3.9 Hz, 1H), 4.89 (d, J=7.5 Hz, 1H), 3.99 (q, J=6.8 Hz, 1H), 3.08-2.87(m, 4H), 2.76-2.57 (m, 1H), 2.49 (ddd, J=15.4, 8.7, 5.2 Hz, 1H), 2.30(ddt, J=13.4, 9.1, 4.8 Hz, 1H), 2.18 (s, 3H), 1.32 (d, J=6.9 Hz, 3H).ESI-MS m/z calc. 472.1947, found 473.36 (M+1)⁺. Chiral HPLC(Chiral PAKIC column, 20% methanol/30% ethanol/50% hexanes; 20 mins, Isocratic): Rt9.973 mins (95% ee). [α]=86.6° (c=0.5, CHCl3)@22.2° C.

Example 2AAA Scheme for the Preparation of Compound 494

Compound 494.(7S)-7,8-dimethyl-4-(methyl-d3)-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-oneStep 1: Ethyl(S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-2-chloro-5-nitro-pyrimidine-4-carboxylate

Ethyl 4-2,6-dichloro-5-nitro-pyrimidine-4-carboxylate ((5 g, 18.8 mmol)and tert-butyl methyl-L-alaninate hydrochloride (4.05 g, 20.67 mmol)were taken into 95% ethanol (50 ml) and triethylamine (2.6 ml, 18.8mmol) and stirred at room temperature for 2 hours. The reaction waspoured into water and extracted with ethyl acetate (3×100 ml). Thecombined extracts were dried over anhydrous magnesium sulfate, filtered,and evaporated in vacuo to provide the title product (5.5 g, 75.3%yield). 1H NMR (400 MHz, DMSO-d6) δ 4.87 (q, J=7.0 Hz, 1H), 4.37 (q,J=7.1 Hz, 2H), 2.86 (s, 3H), 1.46 (d, J=7.1 Hz, 3H), 1.40 (s, 9H), 1.28(t, J=7.1 Hz, 3H).

Step 2: Ethyl(S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-5-nitro-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)pyrimidine-4-carboxylate

(1-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methanaminehydrochloride (935 mg, 3.2 mmol) was added to a solution of Ethyl(7S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-2-chloro-5-nitro-pyrimidine-4-carboxylate(1 g, 2.57 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (40 ml)and heated at reflux for 3 hours. The reaction was cooled to roomtemperature and poured into water and extracted with ethyl acetate(3×100 ml). The combined extracts was dried over magnesium sulfate,filtered, and evaporated in vacuo to provide the title product as ayellow solid (1.56 g, 99.6% yield). 1H NMR (300 MHz, Chloroform-d) δ8.63 (s, 1H), 7.69 (t, J=1.3 Hz, 2H), 7.53 (s, 1H), 7.45 (d, J=11.4 Hz,1H), 5.38 (s, 2H), 4.78 (d, J=7.5 Hz, 1H), 4.50-4.35 (m, 4H), 2.92 (s,3H), 1.51 (s, 3H), 1.43 (s, 9H), 1.40 (d, J=7.1 Hz, 3H). ESI-MS m/z609.5 (M+1)⁺.

Step 3: Ethyl(S)-7,8-dimethyl-6-oxo-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-5,6,7,8-tetrahydropteridine-4-carboxylate

Tin(II) chloride (1.6 g, 8.44 mmol) was added to a solution of ethyl(7S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-5-nitro-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)pyrimidine-4-carboxylatein ethanol (40 ml) and heated to reflux. After 1 hour, an additionaltin(II) chloride (1 g) was added to the reaction and refluxed for 2hours. The reaction was evaporated in vacuo and the residue taken intowater and basified with 1 M sodium hydroxide. The mixture was extractedwith ethyl acetate (2×40 ml). The combined extracts was dried overanhydrous magnesium sulfate, filtered, and evaporated. The crude productwas purified by column chromatography (SiO₂; 40 g) eluting with agradient of 0-10% methanol in dichloromethane. Evaporation of therelevant fractions provided the title product as a yellow solid (0.93 g,72% yield). 1H NMR (300 MHz, Chloroform-d) δ 8.58 (d, J=1.7 Hz, 1H),7.65 (d, J=1.5 Hz, 2H), 7.61-7.49 (m, 1H), 7.44 (s, 1H), 5.36 (s, 2H),5.03 (t, J=5.8 Hz, 1H), 4.14 (q, J=6.9 Hz, 1H), 3.09 (s, 3H), 1.47 (d,J=6.9 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H). ESI-MS m/z calc. 504.1845, found505.33 (M+1)⁺. [α]=58.8° (c=1.0, CHCl3)@22.5° C. Chiral HPLC (ChiralPAKIC column; 20% methanol/30% ethanol/50% hexanes, Isocratic, 25 mins.) Rt25.869 mins. (96.6% ee).

Step 4: Compound 493.(7S)-4-(hydroxymethyl-d2)-7,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

A 0.7 M solution of diisobutyl aluminum deuteride (4 ml, 2.8 mmol) intoluene was added dropwise to a solution of (ethyl(S)-7,8-dimethyl-6-oxo-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-5,6,7,8-tetrahydropteridine-4-carboxylate(410 mg, 0.81 mmol) in THE (10 ml) and stirred at room temperature for 1hour. Water (1 ml) was slowly added to the reaction. Ethyl acetate (10ml) was added and the mixture was filtered through Celite. The filtratewas evaporated in vacuo to afford a yellow solid which was purified bycolumn chromatography (SiO2) eluting with a gradient of 0-10% methanolin dichloromethane. Evaporation of the desired fractions afforded thetitle product as a yellow solid (350 mg, 91% yield). 1H NMR (300 MHz,Chloroform-d) δ 8.55 (d, J=1.9 Hz, 1H), 7.74-7.59 (m, 3H), 7.54 (s, 1H),7.45 (s, 1H), 5.36 (s, 2H), 5.11 (t, J=5.8 Hz, 1H), 4.41 (d, J=5.8 Hz,2H), 4.05 (q, J=6.8 Hz, 1H), 3.46 (s, 1H), 3.03 (s, 3H), 1.40 (d, J=6.8Hz, 3H). ESI-MS m/z calc. 464.18652, found 464.52 (M+1)⁺; [α]=50.72°(c=0.75, acetone)@23° C.

Step 5:(7S)-4-(bromomethyl-d2)-7,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

HBr (5 ml of 33% w/w) was added to a solution of(7S)-4-(hydroxymethyl-d2)-7,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(500 mg, 0.99 mmol) in acetic acid (2 ml) and heated at 110° C. for 1hour. The reaction was evaporated in vacuo to afford the crude productas a dark solid (188 mg) which was used immediately in Step 6.

Step 6: Compound 494.(7S)-7,8-dimethyl-4-(methyl-d3)-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

Sodium borodeuteride (12 mg, 0.29 mmol) was added to a solution of(7S)-4-(bromomethyl-d2)-7,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(75 mg) in DMSO-d6 (3 ml) and stirred overnight at room temperature. Thecrude reaction material was filtered and purified by reverse phase HPLC(C18; 10-95% acetonitrile in water, 0.5 mM HCl) to provide the product.The compound was neutralized by dissolving in dichloromethane andfiltering through a PL-HCO3 cartridge and the filtrate evaporated togive the title product (17.5 mg, 28% yield). 1H NMR (300 MHz,Chloroform-d) δ 8.57 (d, J=1.8 Hz, 1H), 7.81-7.71 (m, 2H), 7.57-7.49 (m,1H), 7.42 (d, J=0.8 Hz, 1H), 5.34 (s, 2H), 4.49-4.31 (m, 2H), 4.03 (q,J=6.9 Hz, 1H), 3.01 (s, 3H), 1.43-1.31 (m, 3H). ESI-MS m/z calc.449.19788, found 449.41 (M+1)⁺. Chiral HPLC (ChiralPAK IC column; 20%methanol/30% ethanol/50% hexanes): Rt 7.885 mins. (82% ee).

Example 2BBB

Compound 487(7S)-4-(hydroxymethyl)-7,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

A 2M solution of lithium aluminum hydride (300 mL, 0.6 mmol) in THE wasadded dropwise to a solution of ethyl(S)-7,8-dimethyl-6-oxo-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-5,6,7,8-tetrahydropteridine-4-carboxylate(see Compound 494, Step 3; 252 mg, 0.5 mmol) in 5 ml of THF and stirredat room temperature for 1 hour. The reaction was quenched by theaddition the dropwise addition of water (1 ml). Ethyl acetate (10 ml)was added to the mixture followed by filtration through celite. Thefiltrate was evaporated in vacuo to afford a crude product which waspurified by column chromatography (SiO₂; 12 g) eluting with a gradientof 0-10% methanol in dichloromethane. The relevant fractions wereevaporated to afford the title product (152 mg (65% yield). 1H NMR (300MHz, Methanol-d4/CDCl3) δ 8.71 (s, 1H), 8.01-7.87 (m, 2H), 7.79 (s, 1H),7.71 (s, 1H), 5.59 (s, 2H), 4.86-4.67 (m, 2H), 4.59 (s, 2H), 4.26 (q,J=6.9 Hz, 1H), 3.55 (t, J=1.1 Hz, 1H), 3.24 (t, J=1.0 Hz, 3H), 1.58 (dt,J=6.9, 1.2 Hz, 3H). ESI-MS m/z calc. 462.17395, found 463.37 (M+1)⁺;[α]=36.7° (c=1.0, THF)@22.7° C. Chiral HPLC (AD-H column, 6×250 mm; 50%isopropanol (0.2% diethylamine)/500% hexanes, Isocratic; 1 ml/min) Rt6.611 mins. (95% ee).

Example 2CCC

Compound 410.(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4-(hydroxymethyl)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-oneStep 1: Ethyl(S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5-nitropyrimidine-4-carboxylate

(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methanamine (2.64 g, 12.86 mmol) wasadded to a solution of ethyl(7S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-2-chloro-5-nitro-pyrimidine-4-carboxylate(2.5 g, 6.43 mmol) and triethylamine (2.7 ml, 19.3 mmol) in ethanol (100ml) and heated at reflux for 3 hours. The reaction was cooled to roomtemperature. The reaction mixture was poured into water (100 ml) andextracted with ethyl acetate (3×150 ml). The combined extracts weredried over magnesium sulfate, filtered, and evaporated in vacuo toprovide the title product that was used immediately withoutpurification.

Step 2: Ethyl(S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridine-4-carboxylate

Ethyl(S)-6-((1-(tert-butoxy)-1-oxopropan-2-yl)(methyl)amino)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5-nitropyrimidine-4-carboxylate(3.5 g, 6.63 mmol) was placed Parr bottle and dissolved in ethanol (50ml) and ethyl acetate (25 ml). 10% Pd/C (300 mg) was placed in thesolution and the was placed on the Parr shaker and charged with 50 psiof hydrogen for 20 hours. The reaction was filtered through celite andthe filtrate evaporated. The resulting crude product was purified bycolumn chromatography (SiO₂) eluting with 0-20% methanol indichloromethane. The desired fractions were combined and evaporated toafford 633 mg (21% yield) of the title product. 1H NMR (400 MHz,DMSO-d6) δ 9.67 (s, 1H), 7.68 (s, 1H), 7.42 (s, 1H), 7.32-7.21 (m, 2H),7.14 (t, J=8.9 Hz, 2H), 7.07 (s, 1H), 5.23 (s, 2H), 4.30 (q, J=7.1 Hz,2H), 3.33 (s, 2H), 3.01 (s, 3H), 1.30 (m, 6H). ESI-MS m/z calc.453.19247, found 454.3 (M+1)⁺.

Step 3: Compound 410.(7S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-4-(hydroxymethyl)-7,8-dimethyl-7,8-dihydropteridin-6(5H)-one

A 1M solution of lithium aluminum hydride (1.5 mL, 1.5 mmol) in THE wasadded dropwise to a solution of ethyl(S)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dimethyl-6-oxo-5,6,7,8-tetrahydropteridine-4-carboxylate(700 mg, 1.45 mmol) in THE (20 ml). The reaction was stirred at roomtemperature for 2 hours. The reaction was quenched by the addition ofmethanol and water and extracted with ethyl acetate. The combinedextracts were dried over magnesium sulfate, filtered, and evaporated.The crude was purified be column chromatography (SiO₂, 12 g) elutingwith a gradient of 0-20% methanol in dichloromethane. The desiredfractions were combined and evaporated in vacuo to provide the titleproduct (208.0 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.68 (br,1H), 7.69 (s, 1H), 7.40 (s, 1H), 7.26 (dd, J=8.5, 5.5 Hz, 2H), 7.15 (t,J=8.7 Hz, 2H), 5.51 (br, 1H), 5.24 (s, 2H), 4.43 (s, 2H), 4.26 (d, J=5.9Hz, 2H), 4.07 (m, 1H), 3.00 (s, 3H), 1.26 (d, J=6.8 Hz, 3H). ESI-MS m/zcalc. 411.18192, found 412.14 (M+1)⁺.

Example 2DDD: Synthesis of Compound 136B (R-isomer of Compound 136):(7R)-4,7,8-trimethyl-2-[[1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazol-4-yl]methylamino]-5,7-dihydropteridin-6-one

Compound 136B was made with same route as Compound 136 but with thecorresponding R starting material A-2. (13.3 g, 84%)¹H NMR (300 MHz,DMSO) δ 9.83 (s, 1H), 8.63 (s, 1H), 7.94-7.79 (m, 2H), 7.76 (s, 1H),7.43 (s, 1H), 6.61 (s, 1H), 5.44 (s, 2H), 4.23 (d, J=6.2 Hz, 2H), 4.00(q, J=6.8 Hz, 1H), 2.94 (s, 3H), 2.13 (s, 3H), 1.19 (d, J=6.8 Hz, 3H).

Example 2EEE: Synthesis of Compound 1B (R-isomer of Compound 1):(7R)-2-[[1-[(4-fluorophenyl)methyl]pyrazol-4-yl]methylamino]-4,5,7,8-tetramethyl-7H-pteridin-6-one

Compound 1B was separated from the racemic mixture in the preparation ofCompound 1 above using SFC separation. ¹H NMR (300 MHz, MeOD) δ 7.66 (s,1H), 7.51 (s, 1H), 7.24 (dd, J=8.6, 5.4 Hz, 2H), 7.05 (dd, J=12.1, 5.4Hz, 2H), 5.26 (s, 2H), 4.46 (s, 2H), 4.18 (q, J=6.9 Hz, 1H), 3.30 (s,3H), 3.13 (s, 3H), 2.39 (s, 3H), 1.27 (d, J=7.0 Hz, 3H).

Example 2FFF: Synthesis of Compound 42B (R-isomer of Compound 42):(R)-7,8-dimethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

Compound 42B was separated from the racemic mixture in the preparationof Compound 42 above using SFC separation. ¹H NMR (300 MHz,Chloroform-d) δ 7.49 (s, 1H), 7.38 (s, 1H), 7.28 (s, 1H), 6.72 (dd,J=7.8, 6.3 Hz, 2H), 5.11 (s, 2H), 4.38 (d, J=5.5 Hz, 2H), 3.97 (q, J=6.8Hz, 1H), 3.00 (s, 3H), 1.35 (d, J=6.8 Hz, 3H).

Example 2GGG: Synthesis of Compound 46B (R-isomer of Compound 46):(R)-2-(((1-(3,5-difluoro-4-methoxybenzyl)-1H-pyrazol-4-yl)methyl)amino)-4,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

Compound 46B was separated from the racemic mixture in the preparationof Compound 46 above using SFC separation. ¹H NMR (300 MHz,Chloroform-d) δ 7.54 (d, J=0.7 Hz, 1H), 7.41-7.34 (m, 1H), 6.73 (dt,J=8.4, 0.8 Hz, 2H), 5.31 (s, 1H), 5.17 (s, 2H), 4.89 (t, J=5.9 Hz, 1H),4.44 (d, J=5.7 Hz, 2H), 4.15-3.94 (m, 4H), 3.05 (s, 3H), 2.23 (s, 3H),1.41 (d, J=6.9 Hz, 3H).

Example 2HHH: Synthesis of Compound 405B (R-isomer of Compound 405):N-[[1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazol-4-yl]methyl]-N-[(7R)-4,7,8-trimethyl-6-oxo-5,7-dihydropteridin-2-yl]acetamide

Compound 405B was prepared from Compound 136B. To a solution of(7R)-4,7,8-trimethyl-2-[[1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazol-4-yl]methylamino]-5,7-dihydropteridin-6-one(250 mg, 0.560 mmol) in anhydrous THF (3.7 mL) was added acetyl acetate(approximately 87 mg, 80.06 μL, 0.84 mmol) and DIEA (approximately 217mg, 293 μL, 1.68 mmol), the mixture was sealed in a microwave tube andheated at 100° C. for 24 hrs. The solvent was removed by evaporation,the residue was purified by silica gel column (40 g) in ISCO elutingwith DCM, 20% MeOH/DCM. The desired fractions were collected andevaporated. The off white solid was dried over 50° C. vacuum forovernight. (206 mg, 75%). First eluting peak SFC: 20% MeOH: 30% EtOH:50% Hexanes (ChiralPac IC)

¹H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.66-8.52 (m, 1H), 7.94-7.77(m, 2H), 7.74 (d, J=0.8 Hz, 1H), 7.35 (d, J=0.7 Hz, 1H), 5.42 (s, 2H),4.93-4.80 (m, 2H), 4.17 (q, J=6.8 Hz, 1H), 2.98 (s, 3H), 2.28 (s, 3H),2.24 (s, 3H), 1.26 (d, J=6.8 Hz, 3H).

Example 2III: Synthesis of Other Compounds of Table 46

The compounds of Table 46 described herein were prepared in a similarmanner as described above for other compounds having R-stereochemistryat the carbon to which R³ and R⁴ are bound (for example, using arespective R-isomer intermediate(s) or by chiral separation (e.g., SFCseparation)).

Compound 9B.(R)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-methyl-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, MeOD) δ 7.66 (s, 1H), 7.51 (s, 1H), 7.24 (dd, J=8.6,5.4 Hz, 2H), 7.05 (dd, J=12.1, 5.4 Hz, 2H), 5.26 (s, 2H), 4.46 (s, 2H),4.18 (q, J=6.9 Hz, 1H), 3.30 (s, 3H), 3.13 (s, 3H), 2.39 (s, 3H), 1.27(d, J=7.0 Hz, 3H). [3], 1H NMR (300 MHz, Methanol-d4) ? 7.57 (s, 1H),7.44 (s, 1H), 7.23-7.12 (m, 2H), 7.05-6.92 (m, 2H), 5.20 (s, 2H), 4.34(s, 2H), 3.99 (q, J=6.9 Hz, 1H), 3.22 (s, 3H), 2.96 (s, 3H), 2.27 (s,3H), 1.10 (d, J=6.9 Hz, 3H). M+1 410.215.

Compound 14B.(R)-4,5,7,8-tetramethyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

M+1 446.19.

Compound 19B.(R)-5,7-diethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-methyl-7,8-dihydropteridin-6(5H)-one

M+1 424.23.

Compound 22B.(R)-8-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7-dimethyl-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, J=1.5 Hz, 2H), 7.37 (d, J=0.8 Hz,1H), 7.26 (dd, J=8.5, 5.7 Hz, 2H), 7.14 (t, J=8.9 Hz, 2H), 6.72 (t,J=6.0 Hz, 1H), 5.24 (s, 2H), 4.35-4.14 (m, 3H), 3.97-3.80 (m, 1H), 3.16(s, 3H), 3.13-3.01 (m, 1H), 1.22 (d, J=6.7 Hz, 3H), 1.12 (t, J=7.1 Hz,3H). [2], 1H NMR (300 MHz, CDCl3) δ 7.45 (d, J=4.9 Hz, 2H), 7.27 (s,1H), 7.16-7.09 (m, 2H), 7.02-6.89 (m, 2H), 5.15 (s, 2H), 4.93 (t, J=5.1Hz, 1H), 4.32 (t, J=7.3 Hz, 2H), 4.09 (dd, J=14.4, 7.6 Hz, 1H), 3.93(dq, J=14.4, 7.2 Hz, 1H), 3.18 (s, 3H), 3.01 (tt, J=12.2, 6.1 Hz, 1H),1.28 (d, J=6.8 Hz, 3H), 1.16-1.06 (m, 3H). M+1 410.3.

Compound 23B.(R)-5,8-dimethyl-7-propyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d4) δ 7.67 (d, J=0.8 Hz, 1H), 7.56-7.48 (m,2H), 6.98-6.86 (m, 2H), 5.26 (d, J=1.0 Hz, 2H), 4.40 (s, 2H), 4.19 (dd,J=5.8, 4.2 Hz, 1H), 3.26 (s, 3H), 3.06 (s, 3H), 1.89-1.71 (m, 2H),1.35-1.09 (m, 2H), 0.87 (t, J=7.3 Hz, 3H). M+1 460.19.

Compound 24B.(R)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,8-dimethyl-7-propyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d4) δ 7.65-7.58 (m, 1H), 7.49 (d, J=6.0 Hz,2H), 7.23 (dd, J=8.6, 5.4 Hz, 2H), 7.10-6.97 (m, 2H), 5.25 (s, 2H), 4.37(s, 2H), 4.25-4.15 (m, 1H), 3.26 (s, 3H), 3.05 (s, 3H), 1.87-1.75 (m,2H), 1.20 (s, 2H), 0.87 (t, J=7.3 Hz, 3H). [2], 1H NMR (300 MHz,Methanol-d4) δ 7.61 (d, J=0.8 Hz, 1H), 7.53-7.44 (m, 2H), 7.28-7.17 (m,2H), 7.10-6.97 (m, 2H), 5.25 (s, 2H), 4.37 (s, 2H), 4.19 (dd, J=5.7, 4.2Hz, 1H), 3.26 (s, 3H), 3.05 (s, 3H), 1.90-1.70 (m, 2H), 1.18 (dtt,J=9.1, 7.3, 6.0 Hz, 2H), 0.87 (t, J=7.3 Hz, 3H). M+1 424.275.

Compound 27B.(R)-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-5,7,8-trimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 7.45 (s, 2H), 7.28 (s, 1H), 7.17-7.05 (m, 2H),7.02-6.86 (m, 2H), 5.15 (s, 2H), 5.00 (s, 1H), 4.39-4.30 (m, 2H), 4.05(q, J=6.8 Hz, 1H), 3.18 (s, 3H), 2.94 (s, 3H), 1.27 (d, J=7.7 Hz, 3H).M+1 396.14.

Compound 30B.(R)-5,8-diethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7-methyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 7.48 (s, 1H), 7.45 (d, J=4.0 Hz, 1H), 7.27 (s,1H), 7.15-7.06 (m, 2H), 6.99-6.88 (m, 2H), 5.15 (s, 2H), 4.95 (dd,J=17.0, 3.5 Hz, 1H), 4.32 (t, J=7.3 Hz, 2H), 4.19-3.60 (m, 4H),3.14-2.92 (m, 1H), 1.25 (t, J=6.9 Hz, 3H), 1.14 (dt, J=14.2, 5.4 Hz,6H). M+1 424.27.

Compound 31B.(R)-5,8-diethyl-7-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=5.9 Hz, 1H), 7.45 (d, J=10.3 Hz,1H), 7.33 (s, 1H), 6.77-6.67 (m, 2H), 5.12 (s, 2H), 4.97 (d, J=5.2 Hz,1H), 4.36 (d, J=5.6 Hz, 2H), 4.10 (q, J=6.8 Hz, 1H), 4.00-3.62 (m, 3H),3.04 (dq, J=14.1, 7.1 Hz, 1H), 1.26 (t, J=7.7 Hz, 3H), 1.14 (dd, J=13.5,7.1 Hz, 6H). M+1 460.28.

Compound 32B.(R)-7-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 7.41 (d, J=6.8 Hz, 1H), 7.40 (s, 1H), 7.31 (s,1H), 7.17-7.05 (m, 2H), 7.01-6.86 (m, 2H), 5.80 (s, 1H), 5.14 (s, 2H),4.65 (d, J=33.9 Hz, 1H), 4.51-4.39 (m, 1H), 4.36 (t, J=6.0 Hz, 2H), 4.15(dt, J=11.3, 5.7 Hz, 1H), 3.18 (s, 3H), 1.85 (dqd, J=15.0, 7.6, 3.4 Hz,1H), 1.74-1.53 (m, 1H), 1.33-1.20 (m, 6H), 0.77 (t, J=7.5 Hz, 3H). [2],1H NMR (300 MHz, CDCl3) δ 7.44 (s, 2H), 7.27 (s, 1H), 7.17-7.09 (m, 2H),7.00-6.89 (m, 2H), 5.15 (s, 2H), 4.96 (s, 1H), 4.44 (dt, J=13.7, 6.8 Hz,1H), 4.34 (d, J=5.6 Hz, 2H), 4.13 (dd, J=7.6, 3.4 Hz, 1H), 3.20 (s, 3H),1.81 (dtt, J=15.1, 7.5, 3.8 Hz, 1H), 1.69-1.57 (m, 1H), 1.25 (t, J=6.5Hz, 6H), 0.78 (t, J=7.5 Hz, 4H). M+1 438.345

Compound 36B.(R)-7-ethyl-8-isopropyl-5-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 7.46 (d, J=3.8 Hz, 1H), 7.45 (s, 1H), 7.32 (s,1H), 6.76-6.69 (m, 2H), 5.12 (s, 2H), 5.05 (s, 1H), 4.46 (dd, J=13.7,6.9 Hz, 1H), 4.37 (d, J=5.7 Hz, 2H), 4.14 (dd, J=7.6, 3.4 Hz, 1H), 3.20(s, 3H), 1.82 (tdd, J=15.1, 7.6, 3.4 Hz, 1H), 1.72-1.56 (m, 1H), 1.26(t, J=6.5 Hz, 6H), 0.78 (t, J=7.5 Hz, 3H). M+1 474.24

Compound 51B.(R)-5-ethyl-8-isopropyl-7-methyl-2-(((1-(3,4,5-trifluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 7.45 (d, J=10.6 Hz, 1H), 7.33(s, 1H), 6.76-6.67 (m, 2H), 5.12 (s, 2H), 5.00 (t, J=5.5 Hz, 1H), 4.54(dq, J=13.2, 6.6 Hz, 1H), 4.35 (t, J=5.8 Hz, 2H), 4.18 (q, J=6.7 Hz,1H), 3.87 (dq, J=14.3, 7.1 Hz, 1H), 3.77-3.58 (m, 1H), 1.19 (m, 12H).M+1 474.34.

Compound 52B.(R)-5-ethyl-2-(((1-(4-fluorobenzyl)-1H-pyrazol-4-yl)methyl)amino)-8-isopropyl-7-methyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H),7.15-7.06 (m, 2H), 6.98-6.88 (m, 2H), 5.15 (s, 2H), 5.01 (t, J=5.1 Hz,1H), 4.54 (hept, J=6.8 Hz, 1H), 4.33 (d, J=5.6 Hz, 2H), 4.24-4.08 (m,1H), 3.93-3.76 (m, 1H), 3.68 (dq, J=14.2, 7.1 Hz, 1H), 2.62 (s, 1H),1.29-1.07 (m, 12H). M+1 438.32.

Compound 186B.(R)-7-ethyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.63 (s, 1H), 7.87 (td, J=7.8,1.5 Hz, 2H), 7.77 (s, 1H), 7.43 (s, 1H), 6.70 (s, 1H), 5.45 (s, 2H),4.24 (d, J=5.9 Hz, 2H), 4.03 (dd, J=6.5, 3.7 Hz, 1H), 2.98 (s, 3H), 2.12(s, 3H), 1.86-1.61 (m, 2H), 0.74 (t, J=7.4 Hz, 3H). M+1 461.47.

Compound 177B.(R)-4,5,7,8-tetramethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.95-7.82 (m, 2H), 7.78 (s,1H), 7.44 (s, 1H), 6.89 (t, J=6.4 Hz, 1H), 5.45 (s, 2H), 4.25 (dd,J=5.8, 2.9 Hz, 2H), 4.02 (q, J=6.8 Hz, 1H), 3.18 (s, 3H), 2.91 (s, 3H),2.27 (s, 3H), 1.04 (d, J=6.9 Hz, 3H). [3], 1H NMR (300 MHz, DMSO-d6) δ8.63 (s, 1H), 7.95-7.82 (m, 2H), 7.78 (s, 1H), 7.44 (s, 1H), 6.87 (t,J=6.1 Hz, 1H), 5.45 (s, 2H), 4.25 (dd, J=6.0, 2.7 Hz, 2H), 4.02 (q,J=6.8 Hz, 1H), 3.18 (s, 3H), 2.91 (s, 3H), 2.27 (s, 3H), 1.04 (d, J=5.8Hz, 3H). M+1 461.315.

Compound 187B.(R)-4,7,8-trimethyl-2-(((1-((3-(trifluoromethyl)pyridin-4-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

M+1 447.28.

Compound 220B.(R)-4,8-dimethyl-7-propyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.70-8.54 (m, 1H), 7.86 (qd,J=8.1, 1.5 Hz, 2H), 7.76 (s, 1H), 7.42 (s, 1H), 6.59 (t, J=5.8 Hz, 1H),5.45 (s, 2H), 4.22 (d, J=6.0 Hz, 2H), 4.00 (dd, J=6.8, 4.0 Hz, 1H), 2.96(s, 3H), 2.11 (s, 3H), 1.83-1.48 (m, 2H), 1.27-1.05 (m, 2H), 0.83 (t,J=7.3 Hz, 3H). M+1 447.28.

Compound 386B.(R)-7-cyclopropyl-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.87 (brs, 1H), 8.63 (d, J=2.3 Hz, 1H),7.96-7.81 (m, 2H), 7.78 (s, 1H), 7.44 (s, 1H), 6.67 (d, J=6.2 Hz, 1H),5.45 (s, 2H), 4.24 (dd, J=5.8, 3.1 Hz, 2H), 3.32 (d, J=9.0 Hz, 1H), 3.03(s, 3H), 2.14 (s, 3H), 0.83 (m, 1H), 0.62-0.27 (m, 4H). M+1 473.23.

Compound 396B.(R)-7-cyclopropyl-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 7.68 (s, 1H), 7.41 (s, 1H),6.61 (t, J=6.1 Hz, 1H), 6.58 (s, 1H), 5.44 (s, 2H), 4.22 (dd, J=6.0, 3.3Hz, 2H), 3.88 (s, 3H), 3.32 (d, J=4.5 Hz, 1H), 3.02 (s, 3H), 2.14 (s,3H), 0.83 (ddt, J=13.2, 8.1, 4.0 Hz, 1H), 0.63-0.27 (m, 4H). M+1 476.55.

Compound 421B.(R)-7-cyclopropyl-2-(((1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.84 (s, 1H), 8.11 (dt, J=2.6, 0.9 Hz,1H), 7.65 (ddd, J=8.3, 7.6, 2.6 Hz, 1H), 7.53 (d, J=0.7 Hz, 1H),7.46-7.35 (m, 1H), 6.98-6.84 (m, 1H), 5.49 (s, 1H), 5.26 (s, 2H), 4.44(dd, J=5.6, 1.7 Hz, 2H), 3.29 (d, J=9.1 Hz, 1H), 3.14 (s, 3H), 2.26 (s,3H), 1.38-1.13 (m, 1H), 1.07-0.90 (m, 1H), 0.76-0.63 (m, 1H), 0.63-0.38(m, 2H). M+1 423.29.

Compound 422B.(R)-2-(((1-((6-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.10 (d, J=2.4 Hz, 1H),7.61 (dd, J=8.5, 2.5 Hz, 1H), 7.54 (s, 1H), 7.38 (s, 1H), 7.25 (d,J=21.3 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 5.25 (s, 2H), 4.91 (d, J=5.8 Hz,1H), 4.42 (d, J=5.7 Hz, 2H), 3.89 (d, J=4.3 Hz, 1H), 3.11 (s, 3H),2.33-2.23 (m, 1H), 2.21 (s, 3H), 1.07 (dd, J=6.9, 1.8 Hz, 3H), 0.97-0.89(m, 4H). M+1 473.41.

Compound 423B.(R)-2-(((1-((6-fluoro-4-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.78 (s, 1H), 7.52 (s,1H), 6.70 (m, 1H), 5.27 (s, 2H), 4.81 (t, J=5.7 Hz, 1H), 4.41 (d, J=5.7Hz, 2H), 3.89 (d, J=4.3 Hz, 1H), 3.11 (s, 3H), 2.38-2.27 (m, 3H),2.26-2.19 (m, 1H), 2.19 (s, 3H), 1.08 (d, J=6.9 Hz, 3H), 0.99-0.81 (m,3H). M+1 439.37.

Compound 445B.(R)-2-(((1-((6-chloropyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7-(2-hydroxyethyl)-4,5,8-trimethyl-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 8.31 (d, J=2.5 Hz, 1H), 7.74 (s, 1H), 7.68(dd, J=8.3, 2.5 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 6.87 (s,1H), 5.32 (s, 2H), 4.64-4.55 (m, 1H), 4.24 (dd, J=6.2, 2.2 Hz, 2H), 4.05(dd, J=7.7, 5.8 Hz, 1H), 3.17 (s, 3H), 2.98 (s, 3H), 2.26 (s, 3H),1.79-1.38 (m, 2H). M+1 457.1.

Compound 495B.(R)-4,8-dimethyl-7-(2,2,2-trifluoroethyl)-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.62 (d, J=1.9 Hz, 1H),7.88-7.79 (m, 2H), 7.75 (s, 1H), 7.42 (s, 1H), 6.60 (t, J=6.0 Hz, 1H),5.44 (s, 2H), 4.40 (dd, J=6.0, 4.0 Hz, 1H), 4.23 (d, J=6.0 Hz, 2H), 2.99(s, 3H), 2.80-2.70 (m, 1H), 2.13 (s, 3H). M+1 515.28.

Compound 497B.(R)-7-ethyl-8-isopropyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, DMSO) δ 10.26 (s, 1H), 8.62 (s, 1H), 7.94-7.78 (m, 2H),7.75 (s, 1H), 7.42 (s, 1H), 7.36 (s, 1H), 6.82 (s, 1H), 5.45 (s, 2H),4.42-4.29 (m, 1H), 4.26 (d, J=5.9 Hz, 2H), 4.07 (dd, J=7.1, 3.2 Hz, 1H),1.85-1.53 (m, 2H), 1.26 (dd, J=6.8, 3.6 Hz, 6H), 0.78 (t, J=7.4 Hz, 3H).M+1 475.37.

Compound 589B.(R)-7-(2-methoxyethyl)-4,8-dimethyl-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Chloroform-d) δ 9.13 (s, 1H), 8.68-8.50 (m, 1H), 7.65(t, J=1.2 Hz, 2H), 7.55 (d, J=0.7 Hz, 1H), 7.42 (d, J=0.7 Hz, 1H), 5.35(s, 2H), 4.92 (t, J=5.8 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 4.15 (dd,J=7.2, 4.2 Hz, 1H), 3.50-3.29 (m, 2H), 3.20 (s, 3H), 3.05 (s, 3H), 2.24(s, 3H), 2.21-1.79 (m, 2H). M+1 491.07.

Compound 678B.(R)-7-(2-methoxyethyl)-4,8-dimethyl-2-(((1-((1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one

¹H NMR (300 MHz, Methanol-d4) δ 7.62 (s, 1H), 7.51 (s, 1H), 6.48 (s,1H), 5.42 (s, 2H), 4.83 (s, 3H), 4.38 (s, 2H), 4.16 (dd, J=6.6, 4.0 Hz,1H), 3.84 (s, 3H), 3.07 (d, J=14.6 Hz, 6H), 2.22-1.89 (m, 5H). M+1494.04.

Compound 204B.(R)-4-((4-(((4,7,8-trimethyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)amino)methyl)-1H-pyrazol-1-yl)methyl)picolinonitrile

¹H NMR (300 MHz, Chloroform-d) δ 8.57 (d, J=5.2 Hz, 1H), 7.52 (s, 1H),7.40 (s, 1H), 7.30 (s, 1H), 7.23-7.10 (m, 1H), 5.45 (s, 1H), 5.26 (s,2H), 4.47-4.31 (m, 2H), 4.00 (q, J=6.7 Hz, 1H), 2.99 (s, 3H), 2.86 (s,3H), 2.17 (s, 3H), 1.34 (d, J=6.8 Hz, 3H). M+1 404.36.

Compound 677B.(R)-7-(hydroxymethyl)-4,8-dimethyl-2-(((1r,3R)-3-(3,4,5-trifluorophenoxy)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one

M+1 424.14.

Example 2JJJ: Synthesis of4,8-dimethyl-7-methylene-2-(((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-pyrazol-4-yl)methyl)amino)-7,8-dihydropteridin-6(5H)-one(Compound 749)

An oven dried flask was charged with(7S)-7-(hydroxymethyl)-4,8-dimethyl-2-[[1-[[6-(trifluoromethyl)-3-pyridiyl]methylamino]-5,7-dihydropteridin-6-one(25 mg, 0.05360 mmol) dissolved in dichloromethane (2 mL) under anatmosphere of nitrogen was added 55 mg (0.08178 mmol) of Martin'ssulfurane(diphenyl-bis[2,2,2-trifluoro-1-phenyl-1-(trifluoromethyl)ethoxy]-λ4}-sulfane).The resulting suspension was stirred at ambient temperature for 1 h. Thereaction was still cloudy. Another 0.5 eq sulfurane reagent was added,and the solution slowly turned clear and blue. After 30 mins, it turnedyellow. LCMS indicated 80% done. Another 0.5 eq sulfurane was added. Thereaction was stirred for 20 mins and turned yellow again. The crudeproduct was loaded directly onto silica gel column (MeOH/DCM 0-50%) toprovide desired product as white solid.

¹H NMR (400 MHz, CDCl₃/Methanol-d₄) δ 8.26 (s, 1H), 7.47 (d, J=8.5 Hz,1H), 7.24 (d, J=8.3 Hz, 1H), 7.30 (s, 1H), 7.24 (d, J=13.7 Hz, 1H), 5.17(s, 1H), 5.12 (s, 2H), 4.35 (s, 1H), 4.16 (s, 2H), 3.10 (s, 3H), 1.99(s, 3H). ESI-MS m/z 444.1634, found 445.36 (M+1)+; 443.46 (M−1)+;Retention time: 0.69 minutes.

Example 2KKK: Synthesis of(S)-2-(((1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)methyl)amino)-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(Compound 795)

Formation of(S)-2-chloro-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one (5)

A suspension of 2,4-dichloro-6-methyl-5-nitro-pyrimidine (26.0 g, 125.0mmol), methyl (2S)-2-(methylamino)butanoate (HCl salt) (23.1 g, 137.5mmol) and NaHCO₃ (52.5 g, 625.0 mmol) in cyclohexane (400 mL) wasequipped with a dean-stark trap. The mixture was heated to reflux for 3h, (4 mL water accumulated in DS trap). Lcms showed desired product. Hotfiltered this solution through celite and washed the cake with hotcyclohexane. The filtrate was concentrated in vacuo. ¹H NMR shows puredesired product 3, with approximately 5% undesired regioisomer (19:1ratio) to afford 37 grams of desired product as a yellow oil.

The oil was dissolved in 300 mL of THF, and added platinum (6.5 g of 3%w/w, 0.9996 mmol). The mixture was placed on a parr shaker and mixedovernight at 50 psi hydrogen. LCMS still shows somehydroxy-intermediate. To the mixture was addedbis[(E)-1-methyl-3-oxo-but-1-enoxy]-oxo-vanadium (approximately 3.314 g,12.50 mmol) and the mixture was placed again into a parr shaker andshaken at 50 psi for 2 more hours. The catalyst was filtered off and theresulting filtrate was concentrated in vacuo. The residue was dissolvedin chloroform (200 mL) and filtered through a plug of florisil. The plugwas eluted with 50% EtOAc/dichloromethane. The filtrate was concentratedin vacuo to a solid containing black impurities. The mixture was dilutedwith TBME 500 mL and stirred for 1 hour, filtered, and washed with TBMEtwice to afford 23 grams of product as a white solid: [α]_(D)=+47.1°,100 mg in 10 mL of CHCl₃, temp 20.9° C.; ¹H NMR (300 MHz, d6-DMSO) δ10.41 (s, 1H), 4.21 (dd, J=6.1, 3.8 Hz, 1H), 3.01 (s, 3H), 2.24 (s, 3H),1.93-1.66 (m, 2H), 0.75 (t, J=7.5 Hz, 3H); ESI-MS m/z calc. 240.08,found 241.17 (M+1)⁺; 239.17 (M−1)⁻; Retention time: 0.6 minutes.Formation of 1-(3,3-difluorocyclobutyl)-1H-pyrazole-4-carbonitrile (6)

Step 1: To a solution of 1H-pyrazole-4-carbonitrile (10.0 g, 107.4 mmol)in dichloromethane (80 mL) was added pyridine (17.4 mL, 215.1 mmol). Themixture was cooled (0° C.). A separate mixture oftrifluoromethylsulfonyl trifluoromethanesulfonate (20 mL, 118.9 mmol) indichloromethane (2 0 mL) was slowly added to the first mixture, keepinginternal temperature below 30° C. The mixture was stirred at thistemperature for 30 minutes. The mixture was quenched with aqueoussaturated NH₄Cl solution (100 mL). Split layers and wash organic layerwith sat NaHCO₃ (100 mL), water, brine (100 mL each), dry, filter andremove solvent under reduced pressure. Added water (50 mL) to theresidue and agitated for 60 minutes. Filtered resulting solid and driedo/n under vacuum to afford 18.5 grams of desired product: ¹H NMR (400MHz, CDCl₃) δ 8.60-8.41 (m, 1H), 8.14 (s, 1H); ESI-MS m/z calc.224.98198, Retention time: minutes.

Step 2: To a solution of 3,3-difluorocyclobutanol (1.06 g, 9.81 mmol) inacetonitrile (10 m L) was added Cs₂CO₃ (3.5 g, 10.74 mmol). The mixturewas cooled to 0° C. A solution of the previousintermediate-1-(trifluoromethylsulfonyl)pyrazole-4-carbonitrile (2.0 g,8.9 mmol) in acetonitrile (10 mL) was slowly added to reaction mixturekeeping temperature below 30° C. The mixture was warmed to roomtemperature and stirred for 30 minutes. Filtered solids and removesolvent under reduced pressure. Partition residue betweendichloromethane and water (30 mL each). Split layers and washed organicwith brine, dry, filter and remove solvent under reduced pressure. Theresulting residue was purified via silica gel chromatography (Isco 80 ggold gradient 0-100% EtOAc/heptanes) product elutes about 35-40% EA/Hepand only visible under all wavelength to afford 1.38 grams of desiredproduct: ¹H NMR (400 MHz, CDCl₃) δ 7.90 (d, J=4.3 Hz, 2H), 4.88-4.66 (m,1H), 3.42-3.08 (m, 4H). Formation of(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)methanamine (7)

To a solution of 1-(3,3-difluorocyclobutyl)pyrazole-4-carbonitrile, 6,(4.4 g, 22.82 mmol) in MeO H (30 mL) was added 7N ammonia in methanol(30 mL). Washed Raney nickel (750 mg, 12.78 mmol) with water (˜4×10 mL)than added to reaction mixture. Put on Parr shaker and pressurized to 50psi hydrogen and allowed to react for 4 hours. Filtered through Celiteand removed solvent under reduced pressure. Stripped from diethyl ether(3×100 mL) and placed on vacuum overnight to afford 4.6 grams of desiredproduct: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (s, 1H), 7.40 (s, 1H), 4.67 (dq,J=14.6, 7.3 Hz, 1H), 4.09-3.63 (m, 2H), 3.38-2.95 (m, 4H); ESI-MS m/zcalc. 187.09, found 188.12 (M+1)⁺; Retention time: 0.51 minutes. Used innext step without further purification.

Formation of(S)-2-(((1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)methyl)amino)-7-ethyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(I-795)

To (7S)-2-chloro-7-ethyl-4,8-dimethyl-5,7-dihydropteridin-6-one, 5,(1.94 g, 8.05 mmol),[1-(3,3-difluorocyclobutyl)pyrazol-4-yl]methanamine, 7, (1.51 g, 8.05mmol), (tBuXPhos Pd G1) (200 mg, 0.29 mmol) in tBuOH (50.77 mL) undernitrogen was added NaOtBu (approximately 15.1 mL of 2 M, 30.18 mmol).The mixture was stirred for 20 minutes. The mixture was diluted withaqueous saturated NH₄Cl solution and extracted with dichloromethane(3×), dried, stirred with TMP resin. The solution was evaporated andpurified by silica gel chromatography (0 to 20% M eOH indichloromethane) to afford 3.05 g of desired product: [α]_(D)=34.31 (c0.51, MeOH); ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.56 (s, 1H), 7.44(s, 1H), 4.83 (t, J=5.7 Hz, 1H), 4.72-4.55 (m, 1H), 4.43 (d, J=5.8 Hz,2H), 4.08 (dd, J=6.5, 3.7 Hz, 1H), 3.36-3.08 (m, 7H), 3.08 (d, J=6.1 Hz,3H), 2.23 (s, 3H), 2.09-1.91 (m, 1H), 1.92-1.80 (m, 1H), 0.92 (t, J=7.5Hz, 3H); ESI-MS m/z calc. 391.19, found 392.23 (M+1)⁺; Retention time:0.69 minutes; Chiral HPLC ee>99.5%.

Example 2LLL: Synthesis of(S)-7-isopropyl-4,8-dimethyl-2-(((1s,3R)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one(Compound 1417)

Formationof(S)-2-chloro-7-isopropyl-4,8-dimethyl-7,8-dihydropteridin-6(5H)-one(1)

To a 2-L round bottom flask was added2,4-dichloro-6-methyl-5-nitro-pyrimidine (55.0 g, 256.5 mmol), NaHCO₃(108.4 g, 1.290 mol), and cyclohexane (600 mL). Let stir to dissolvepyrimidine (5 min), then added methyl(2S)-3-methyl-2-(methylamino)butanoate (Hydrochloride salt) (49.0 g,256.2 mmol). The flask was equipped with a Dean-Stark trap and thereaction was heated to 110° C. LC-MS (UPLC_CSH_C18_5to95_ACN_TFA_1p4min) showed reaction complete after 2.5 h. The mixture was stirred foranother 30 min, filtered reaction hot through Celite and washed solidwith 1 L hot cyclohexane. Concentrated mixture to a yellow oil. 1H NMRshowed pure. In a 2-L Parr bottle was added platinum (13.34 g of 3% w/w,2.051 mmol). Dissolved oil in THE (550 mL) and added to Parr bottleunder N2. The bottle was placed on a Parr shaker under 50 psi of H2. TheParr shaker was refilled to 50 psi several times. Let go overnight.LC-MS showed small amt of dechlorinated intermediate. Addedbis[(E)-1-methyl-3-oxo-but-1-enoxy]-oxo-vanadium (1.36 g, 5.129 mmol)and placed the bottle on the Parr shaker under 50 psi of H2. The Parrshaker was refilled to 50 psi three times. After 5 h, no moreconsumption of H2. Filtered rxn through Florisil and eluted withEtOAc/DCM (1:1) until no more material was detected by UV (˜4 L).Concentrated filtrate. Yellow solid. Stirred resulting solid with MTBE(1 L) for 2 h. Filtered and washed white solid with MTBE (2×250 mL).Dried under vacuum in funnel.

Optical rotation: CHCl₃, 100 mg/10 mL conc, [α]_(D)=118.12°, temp=22.8°C. Chiral HPLC: AD-H column, 4.6 mm×2 50 mm, 40% EtOH/hex isocraticgradient, 20 min run, >99% ee.(7S)-2-chloro-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one (57.75g, 88%). ¹H NMR (300 MHz, Chloroform-d) δ 9.32 (s, 1H), 3.96 (d, J=4.1Hz, 1H), 2.35 (s, 3H), 2.32-2.18 (m, 1H), 1.08 (d, J=6.9 Hz, 3H), 0.92(d, J=6.9 Hz, 3H). ESI-MS m/z calc. 254.09, found 255.12 (M+1)⁺;Retention time: 0.63 minutes.

Formation of tert-butyl((1s,3s)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)-cyclobutyl)carbamate(3)

To cis-tert-butyl N-[3-(hydroxymethyl)cyclobutyl]carbamate (5.8 g, 28.82mmol) and triphenylphosphane (9.1 g, 34.7 mmol) in THE (80 mL) at roomtemp was added ethyl (NE)-N-ethoxycarbonyliminocarbamate (15.8 mL of 40%w/w, 34.69 mmol), followed by 2-(trifluoromethyl)pyrimidin-5-ol (5 g,30.47 mmol). The reaction mixture was stirred at room temperature for 1h. THE was removed, added 100 mL DCM, washed with 2 N NaOH twice. Theorganic phase was concentrated in vacuo. The resulting residue waspurified by silica gel chromatography using EtOAc/heptanes to afford8.17 grams of desired product: ¹H NMR (400 MHz, Chloroform-d) δ 8.51 (s,2H), 4.72 (s, 1H), 4.11 (d, J=5.5 Hz, 2H), 2.67-2.41 (m, 3H), 1.84-1.74(m, 1H).

Formation of(1s,3s)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)cyclobutan-1-amine(4)

To tert-butylN-[3-[[2-(trifluoromethyl)pyrimidin-5-yl]oxymethyl]cyclobutyl]carbamate,3, (8.17 g, 23.51 mmol) in Methanol (20 mL) was added hydrogen chloride(27 mL of 4 M solution, 108.0 mmol) in dioxane at room temperature. Stirat 50° C. for 30 minutes. The organics were evaporated and the resultingresidue was washed with ether-heptane to afford 6.5 g of desired productas HCl salt: ¹H NMR (300 MHz, Methanol-d4) δ 8.61 (s, 2H), 4.20 (d,J=5.5 Hz, 2H), 3.73 (tt, J=8.7, 7.6 Hz, 1H), 2.77-2.60 (m, 1H),2.57-2.40 (m, 2H), 2.24-1.94 (m, 2H); ESI-MS m/z calc. 247.09, found248.17 (M+1)⁺; Retention time: 0.58 minutes.

Formation of(S)-7-isopropyl-4,8-dimethyl-2-(((1s,3R)-3-(((2-(trifluoromethyl)pyrimidin-5-yl)oxy)methyl)cyclobutyl)amino)-7,8-dihydropteridin-6(5H)-one(I-1417)

To (7S)-2-chloro-7-isopropyl-4,8-dimethyl-5,7-dihydropteridin-6-one, 1,(1.43 g, 5.56 mmol),3-[[2-(trifluoromethyl)pyrimidin-5-yl]oxymethyl]cyclobutanamine, 4,(Hydrochloride salt) (1.57 g, 5.52 mmol), (tBuXPhos Pd G1) (200 mg,0.2913 mmol) in ^(t)BuOH (30 mL) under an atmosphere of nitrogen wasadded NaOtBu (12.5 mL of 2 M, 25.00 mmol). The mixture was stirred for20 minutes then diluted into 80 mL of aqueous saturated NH₄Cl solution.The mixture was extracted with dichloromethane (3×60 mL), dried, stirredwith TMP resin. The organic phase was concentrated in vacuo and purifiedby silica gel chromatography (0 to 20% MeOH/DCM gradient) to afford 2.62grams of desired product: [α]_(D)=39.69 (c 1.04, MeOH); ¹H NMR (400 MHz,CDCl₃) δ 8.52 (s, 2H), 7.69 (s, 1H), 4.82 (d, J=7.5 Hz, 1H), 4.43 (dd,J=16.3, 8.8 Hz, 1H), 4.14 (d, J=5.7 Hz, 2H), 3.90 (d, J=4.3 Hz, 1H),3.14 (s, 3H), 2.74-2.60 (m, 2H), 2.62-2.50 (m, 1H), 2.32-2.20 (m, 1H),2.19 (s, 3H), 1.94-1.75 (m, 2H), 1.30 (s, 2H), 1.08 (d, J=7.0 Hz, 3H),0.93 (d, J=6.9 Hz, 3H). ESI-MS m/z calc. 465.21, found 466.27 (M+1)⁺;Retention time: 0.79 minutes.

Example 3: PLK1 Inhibition Assay

Compounds were screened for their ability to inhibit Plk1 using aradioactive-phosphate incorporation assay. Assays were carried out in amixture of 25 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, and 2 mM DTT.Final substrate concentrations were 20 μM [γ-33P]ATP (35mCi 33P ATP/mmolATP, Perkin Elmer/Sigma Chemicals) and 9 uM Sam68 protein. Assays werecarried out at room temperature in the presence of 15 nM Plk1. An assaystock buffer solution was prepared containing all of the reagents listedabove, with the exception of ATP and the test compound of interest. 0.75μL of DMSO stock containing serial dilutions of the test compound(typically starting from a final concentration of 10 μM with 2-foldserial dilutions—final DMSO concentration 1.5%) was placed in a 384 wellplate followed by addition of 25 μL [y-33P]ATP (final concentration 20μM). The reaction was initiated by addition of 25 μL of the assay stockbuffer solution.

The reaction was stopped after 45 minutes by the addition of 25 μL 30%trichloroacetic acid (TCA) containing 10 mM cold ATP. The entirequenched reaction was transferred to a 384-well glass fiber filter plate(Millipore, Cat no. MZFBNOW50). The plate was washed with 3×5% TCA.After drying, 40 μL of Ultima Gold liquid scintillation cocktail (PerkinElmer) was added to the well prior to scintillation counting in aPerkinElmer TopCount.

After removing mean background values for all of the data points,Ki(app) data were calculated from non-linear regression analysis of theinitial rate data using the Prism software package (GraphPad Prism,GraphPad Software, San Diego Calif., USA). The data is summarized inTable 45.

Example 4: Colo 205 Reporter Assay

The compounds of the invention described herein were screened using theassay procedure for β-catenin-TCF-mediated reporter transcriptionactivity described below.

In cells with activated WNT signaling, we have found that induction ofER Stress by the mechanism of these compounds results in a rapidreduction in the activity of this reporter gene and that the activity inthe assay correlates with the activity of these compounds as inducers ofER Stress and the UPR, and all other measures of specific activity ofthese compounds, including calcium release, viability, and displacementof radiolabeled version of these compounds from their specific bindingsite in cells.

Reporter cell lines were generated by stably transfecting cells ofcancer cell lines (e.g., colon cancer) with a plasmid reporter construct(From SABiosciences, a QIAGEN company) that includes TCF/LEF promoterdriving expression of the firefly luciferase gene. TCF/LEF reporterconstructs were made in which TCF/LEF promoter, a promoter with optimalnumber of TCF/LEF binding sites designed by SABiosceinces, was linkedupstream of the firefly luciferase gene. This construct could alsoinclude a puromycin resistance gene as a selectable marker. Thisconstruct could also be used to stably transfect Colo 205 cells, a coloncancer cell line having a mutated APC gene that causes a constitutivelyactive β-catenin. A control cell line was generated using anotherplasmid construct containing the luciferase gene under the control of aCMV basal promoter which is not activated by p-catenin.

Colo 205 Cultured cells with a stably transfected reporter constructwere plated at approximately 10,000 cells per well into 384 wellmulti-well plates for twenty four hours. The testing compounds were thenadded to the wells in 2-fold serial dilutions using a twenty micromolartop concentration. A series of control wells for each cell type receivedonly compound solvent. Five hours after the addition of compound,reporter activity for luciferase was assayed, by addition of theSteadyGlo luminescence reagent (Promega). The reporter luminescenceactivity was measured using Pherastar plate reader (BMG Labtech).Readings were normalized to DMSO only treated cells, and normalizedactivities were then used in the IC50 calculations. The Colo 205reporter assay data are summarized in Table 45: A<0.3 μM; 0.3 μM≤B<1.0μM; 1.0 μM≤C<K5.0 μM; D≥5.0 μM.

TABLE 45 PLK1 and Colo 205 Reporter Assay Data PLK1 - 33P.ENZ - TCFreporter TCF reporter Comp. CB 10 Ki Colo205 Comp. Colo205 # (uM) IC₅₀(uM) # IC₅₀ (uM) 1 >4 A 410 2 >4 A 412 A 3 >4 A 413 A 4 >4 A 414 A 5 >4B 415 A 6 >4 B 416 A 7 >4 B 417 A 8 >4 B 418 A 9 >4 A 419 A 10 — D 420 A11 — D 421 A 12 — B 422 A 13 — D 423 A 14 >4 A 424 A 15 >4 A 425 A 16 —A 426 A 17 — A 427 B 18 — A 428 D 19 >4 B 429 A 20 — B 430 A 21 — A 431A 22 >4 A 432 A 23 >4 A 433 A 24 >4 B 434 A 25 — A 435 A 26 — A 436 A 27— B 437 A 28 — A 438 A 29 — A 439 D 30 >4 A 440 A 31 — A 441 A 32 >4 B442 A 33 — B 443 B 34 >4 B 444 B 35 — A 445 B 36 — A 446 A 37 — A 447 A38 — A 448 A 39 — — 449 A 40 — C 450 A 41 — B 451 A 42 — A 452 A 43 — D453 A 44 >4 A 454 A 45 — A 455 A 46 >4 A 456 A 47 >4 A 457 A 48 >4 A 458B 49 — A 459 D 50 >4 D 460 A 51 >4 A 461 C 52 — B 462 C 53 — A 463 D54 >4 A 464 B 55 — A 465 B 56 — A 466 A 57 — A 467 A 58 — A 468 A 59 — D469 A 60 — D 470 A 61 — A 471 D 62 — D 472 A 63 — A 473 A 64 — A 474 C65 — A 475 C 66 — A 476 C 67 — A 477 A 68 — A 478 C 69 — A 479 A 70 — B480 A 71 — B 481 B 72 — A 482 D 73 — A 483 C 74 — B 484 C 75 — A 485 A76 — D 486 C 77 — A 487 B 78 — A 488 C 79 — A 489 D 80 — A 490 D 81 — A491 A 82 — B 492 B 83 — A 493 C 84 — A 494 A 85 — A 495 A 86 — A 496 A87 — A 497 B 88 — A 498 A 89 — A 499 A 90 — A 500 A 91 — A 501 A 92 — A502 C 93 — B 503 C 94 — A 504 B 95 — A 505 C 96 — A 506 B 97 — A 507 A98 — C 508 B 99 — D 509 B 100 — C 510 A 101 — A 511 A 102 — C 512 A 103— A 513 A 104 — A 514 A 105 — A 515 A 106 — A 516 A 107 — A 517 A 108 —B 518 A 109 — C 519 C 110 — B 520 D 111 — B 521 C 112 >4 A 522 A 113 >4A 523 D 115 — C 524 D 116 >4 A 525 D 117 — A 526 D 118 — D 527 B 119 — C528 A 120 — B 529 C 121 — C 530 D 122 — A 531 B 123 — A 532 B 124 — B533 B 125 — C 534 A 126 — C 535 A 127 — B 536 A 128 — C 537 C 129 — B538 C 130 — D 539 B 131 — C 540 C 132 — B 541 B 133 — A 542 A 134 — A543 C 135 — A 544 A 136 >4 A 545 B 137 — A 546 D 138 >4 A 547 C 139 — C548 B 140 — A 549 C 141 — A 550 A 142 — B 551 A 143 — B 552 D 144 — A553 B 145 — A 554 C 146 — A 555 C 147 — A 556 A 148 — B 557 A 149 — A558 C 150 — A 559 C 151 — A 560 D 152 — A 561 A 153 — A 562 B 154 — A563 A 155 — A 564 C 156 — A 565 A 157 — A 566 A 158 — A 567 A 159 — B568 A 160 >4 A 569 C 161 — B 570 A 162 — D 571 B 163 — C 572 A 164 — C573 A 165 — D 574 A 166 — D 575 A 167 — A 576 A 168 — A 577 B 169 — A578 A 170 — A 579 C 171 — A 580 B 172 — A 581 A 173 — C 582 B 174 — A583 A 175 — A 584 D 176 — B 585 B 177 — A 586 A 178 — C 587 B 179 — A588 A 180 — A 589 A 181 — A 590 B 182 — A 591 A 183 — A 592 D 184 — A593 A 185 — B 594 C 186 — A 595 B 187 — A 596 A 188 — A 597 C 189 — A598 A 190 — B 599 A 191 — C 600 C 192 >4 A 601 B 193 — B 602 B 194 — A603 B 195 — B 604 C 196 — B 605 D 197 — A 606 B 198 — C 607 A 199 — A608 A 200 — B 609 C 201 — B 610 D 202 — D 611 D 203 — A 612 A 204 — D613 B 205 — B 614 C 206 — A 615 B 207 — A 616 B 208 — A 617 D 209 — A618 B 210 — A 619 C 211 — B 620 D 212 — D 621 B 213 — A 622 A 214 — D623 B 215 — A 624 D 216 — D 625 D 217 — D 626 A 218 — A 627 C 219 — A628 D 220 — A 629 A 221 >4 A 630 C 222 — D 631 D 223 >4 A 632 B 224 >4 A633 C 225 — D 634 D 226 — A 635 A 227 — B 636 D 228 — C 637 D 229 >4 A638 D 230 — B 639 C 231 — A 640 D 232 — A 641 D 233 — A 642 D 234 >4 B643 A 235 — A 644 A 236 — A 645 A 237 — B 646 A 238 — A 647 A 239 — A648 A 240 — C 649 A 241 — D 650 A 242 — A 651 C 243 — C 652 B 244 — D653 D 245 — D 655 A 246 >4 A 656 A 247 >4 C 657 A 248 — A 658 A 249 — A659 A 250 — B 660 A 251 — B 661 A 252 — A 662 B 253 >4 A 663 C 254 >4 A664 B 255 — A 665 B 256 — B 666 B 257 — A 667 A 258 — C 668 A 259 — D669 A 260 — B 670 A 261 — A 671 A 262 — C 672 A 263 — B 673 B 264 — A674 A 265 — B 675 B 266 — B 676 A 267 >4 A 677 A 268 >4 B 678 A 269 A679 B 270 — B 680 B 271 — A 681 B 272 — A 682 A 273 — A 683 B 274 — D684 A 275 >4 A 685 A 276 — D 686 A 277 — A 687 B 278 — C 688 A 279 — B689 B 280 — A 690 A 281 — A 691 A 282 — A 692 B 283 — A 693 D 284 — A694 A 285 — A 695 A 286 — A 696 B 287 — A 697 B 288 — B 698 B 289 — D699 C 290 — D 703 B 291 — A 704 A 292 — A 705 A 293 — A 706 B 294 — A707 B 295 — A 708 A 296 — A 709 B 297 — D 710 C 298 — C 711 A 299 — B712 A 300 — D 713 A 301 — A 714 A 302 — C 715 C 303 — B 716 A 304 — B717 C 305 — B 718 A 306 — C 719 A 307 — C 720 B 308 — C 721 C 309 — B722 C 310 — C 723 A 311 >4 A 724 B 312 — A 725 A 313 — D 726 C 314 — B727 A 315 — A 728 A 316 — D 729 A 317 — B 730 C 318 — D 731 D 319 — D732 C 320 — C 733 D 321 — B 734 B 322 — B 735 A 323 — A 736 B 324 — A737 C 325 — B 738 B 326 — A 739 B 327 — A 740 B 328 — A 741 B 329 — A742 C 330 — B 743 C 331 — A 744 B 332 — A 745 B 333 — A 746 B 334 — B747 B 335 >4 A 748 A 336 — B 749 C 337 — B 795 A 338 — C 1417 A 339 — B— 340 — A — 341 — A — 342 — C — 343 — D — 344 — B — 345 — B — 346 — B —347 — A — 348 — C — 349 — D — 350 — B — 351 — C — 352 — C — 353 — D —354 — C — 355 — C — 356 — B — 357 — C — 358 — C — 359 — A — 360 — A —361 — A — 362 — B — 363 — A — 364 — A — 365 — A — 366 — A — 367 — A —369 — D — 370 — A — 371 — D — 372 — D — 373 — B — 374 — D — 375 — A —376 — C — 377 — A — 381 — B — 382 — A — 383 — A — 384 — A — 385 — A —386 — A — 387 — A — 388 — A — 389 — A — 390 — A — 394 — A — 395 — A —396 — A — 397 — A — 398 — A — 400 — A — 401 — D — 402 — D — 403 — D —404 — D — 405 — D — 406 — D — 407 — D — 408 — A 409 — A

Example 5

Colo 205 reporter assay data has also been obtained for certainR-isomers of Formula (I) wherein R⁴ is —H or -D, and wherein the carbonto which R³ and R⁴ are attached (C2 carbon of Formula (X)) has Rstereochemistry; such epimeric compounds are represented using thesuffix “B” attached to the Compound described herein having the Sstereochemistry at the carbon to which R³ and R⁴ are attached:

These assay data for the R-stereoisomers are summarized in Table 46below, where A<0.3 μM; 0.3 μM≤B<1.0 μM; 1.0 μM≤C<5.0 μM; D≥5.0 μM.

TABLE 46 Colo 205 Reporter Assay Data R-isomer at C2 Compound(Corresponding TCF reporter Colo205 TCF No. to C2 S-isomer) reporterColo205 IC₅₀ (μM)* I-866  1B B I-1634  9B D I-1229  14B A I-987  19B AI-860  22B A I-1348  23B A I-984  24B B I-809  27B B I-985  30B A I-1349 31B A I-1146  32B B I-1465  36B A I-1463  51B A I-1144  52B B I-896 42B B I-1205  46B A I-1635 186B C* I-1363 177B B* I-1636 136B C* I-1637187B C* I-1638 220B C* I-1639 386B C* I-1640 405B D* I-1498 396B B*I-1641 421B D* I-1642 422B C* I-1643 423B C* I-1644 445B C* I-1645 495BC* I-1646 497B D* I-1647 589B C* I-1648 678B D* I-1649 204B D* I-1650677B C*

Example 6: HepG2 XBP1 Reporter Assay

HepG2 hepatoma cells were transduced with a retrovirus encoding the cDNAfor unspliced (u) XBP1, which contains a non-processed intron, fused tothe cDNA for firefly luciferase. Upon induction of ER stress, thenon-processed intron of XBP1(u) is spliced out by active IRE1alphaendonuclease. The resulting spliced (s) XBP1 is now in frame withluciferase which causes the production of active luciferase protein,resulting in bioluminescence

HepG2 XBP1(u)-Luc cells were plated Colo 205 Cultured cells with astably transfected reporter construct were plated at approximately30,000 cells per well into 96 well multi-well plates for twenty fourhours. The testing compounds were then added to the wells in 3-foldserial dilutions using a twenty seven micromolar top concentration. Aseries of control wells for each cell type received only compoundsolvent. Six hours after the addition of compound, reporter activity forluciferase was assayed, by addition of the SteadyGlo luminescencereagent (Promega). The reporter luminescence activity was measured usingPherastar plate reader (BMG Labtech). Readings was normalized to DMSOonly treated cells, and normalized activities were then used in the IC50calculations. The HepG2 XBP1 reporter assay data are summarized in Table47: A<0.6 μM; 0.6 μM≤B<2.0 μM; 2.0 μM≤C<10.0 μM; D≥10.0 μM.

TABLE 47 Hek293 HepG2 HepG2 empty Hek293 WFS1 Comp. Calcium RadioligandXBP1 vector WFS1 HepG2 KO No. Flux^(A) Displacement^(B) Reporter^(C)viability^(D) viability^(D) viability^(E) viability^(E) 170 A B A D A A— 388 A A A D A — — 122 A A A D A — — 254 B B A — — — — 149 A B A D A A— 332 B B A D A — — 292 A A A — — — — 311 A B A D A D — 386 B B A D A —— 430 B A A D A A D 418 A A A D A A D 416 B A A D A A D 154 A A A D A —— 324 A A A D A — — 335 B A A D A C — 424 B A A D A A D 80 B A A D A — —186 B B A D A — — 412 B A A D B C D 356 B C A D A D — 188 B B A D A — —385 B A A D A — — 160 B B A D A — — 397 B B A D A — — 409 B A A D A A D423 B B A D A A D 96 A A A D B C D 310 C C A D B D — 421 B B A D B B D207 B B A D A — — 396 B B A D A — — 329 B B A D A — — 83 A A B D A — —395 B B B D A — — 174 B B B D A — — 384 B B B D A A — 136 B B B D A B D9 B B B D B D D 415 B A B D A B D 398 B B B D A B — 425 B B B D B B D 7B B B D B C D 376 B B B D B — — 383 B A B D A A — 142 B B B D B — — 6 BB B D B C D 427 B A B D B D D 377 A A B D A — — 94 B B B D A — — 307 B BB D B C — 237 B B B D B D — 305 B B C D B D — 357 B B C D B C — 420 C BC D B B D 8 C C C D D C D 419 C B C D B C D 143 C B C D B — — 173 C C CD B — — 128 C D C D C C D 164 C B C D C D D 121 B B C D C D D 247 C B DD D C D 115 C C D D C D D 125 C B D D C C D 163 C D D D D D D 139 C C DD D D D 222 C C D D D D D 428 D D D D D D D 405 D D D D D D — 403 D D DD D D — 1 A B — D A A D 272 B B — D A A — 253 A A — D A B — 257 B B — DA C — 258 B B — D B C — 4 A B — D A C — 251 B B — D B D — 46 A A — D A —— 246 D B — D A — — 77 B B — D B — — 250 B B — D B — — 684 A A — — — — —686 A A — — — — — 711 A A — — — — — 685 A A — — — — — 551 A A — — — — —643 A A — — — — — 716 B A — — — — — 677 — B — — — — — 717 C B — — — — —723 B B — — — — — 216 D D — — — — — 795 A B A — — — — 1417 A B A — — — —^(A)Scale for Calcium Flux Assay Data: A < 0.6 μM; 0.6 μM ≤ B < 2.0 μM;2.0 μM ≤ C < 10.0 μM; D ≥ 10.0 μM. ^(B)Scale for RadioligandDisplacement Assay Data: A < 0.06 μM; 0.06 μM ≤ B < 0.6 μM; 0.6 μM ≤ C <3.0 μM; D ≥ 3.0 μM. ^(C)Scale for HepG2 XBP1 Reporter Data: A < 0.6 μM;0.6 μM ≤ B < 2.0 μM; 2.0 μM ≤ C < 10.0 μM; D ≥ 10.0 μM. ^(D)Scale forHek293 empty vector and WFS1 over-expressing cell data: A < 0.06 μM;0.06 μM ≤ B < 0.6 μM; 0.6 μM ≤ C < 3.0 μM; D ≥ 3.0 μM. ^(E)Scale forHepG2 parental and WFS1 knockout cell data: A < 0.5 μM; 0.5 μM ≤ B < 2.0μM; 2.0 μM ≤ C <10.0 μM; D ≥ 10.0 μM.

Example 7: Calcium Flux Assay

Compounds described herein induced ER stress by causing intracellularcalcium flux. Calcium flux was measured in Colo-205 cells using theFLIPR® Calcium 5 Assay Kit according to manufacture's protocol(Molecular Devices, Cat. #R8186) on a FLIPR3 system (Molecular Devices).Calcium flux is measured over 36 minutes. The Colo-205 calcium fluxassay data are summarized in Table 47: A<0.6 μM; 0.6 μM≤B<2.0 μM; 2.0μM≤C<10.0 μM; D≥10.0 μM.

Example 8: Membrane Extraction Protocol

Cell pellets were re-suspended in 15 times packed cellular volume in 4°C. hypotonic lysis buffer (10 mM HEPES, pH 7.5 containing 1× Proteaseinhibitor, 0.5 mM EDTA and 2 mM DTT). Re-suspended cells werehomogenized with 6-8 strokes in a dounce homogenizer kept on ice.Lysates were centrifuged at 500×G for 15 minutes at 4° C. without braketo decelerate rotor. Following centrifugation, remove the supernatant toa fresh tube and place on ice (Supernatant 1). Repeat the above steps onthe lysed cell pellet using 0.5 the original volume of hypotonic lysisbuffer and remove the 500×G supernatant (Supernatant 2) and combine withSupernatant 1. Transfer the combined supernatants to a 45-Tiultracentrifuge tube and centrifuge at 100,000×G for 30 minutes.Following ultracentrifugation, carefully remove the supernatant anddiscard. Resuspend the 100,000×G pellet in cold resuspension buffer (10mM HEPES, pH 7.5, 300 mM NaCl containing 1× Protease inhibitor, 1× EDTAand 2 mM DTT). Centrifuge sample at 500×G for 10 minutes with no brakeand remove any cloudy, flocculent material. Resuspend pellet inresuspension buffer to approximately 2 mg/mL of protein concentrationfor use in radioligand binding assay and immunoblotting.

Example 9: Radioligand Displacement Assay

Radiolabeled Compound 136 (tritiated Compound 136) was shown tospecifically bind cellular membrane extracts which over-express WFS1.The binding affinities of compounds were determined by measuring thecompetitive displacement of a tritiated Compound 136 probe from purifiedHEK293 membranes over-expressing WFS-1. The data for the radioliganddisplacement assay are summarized in Table 47: A<0.06 μM; 0.06 μM≤B<0.6μM; 0.6 μM≤C<3.0 μM; D≥3.0 μM.

The assay was performed in 50 μl assay volume containing a finalconcentration of 20 mM HEPES, pH 7.5, 300 mM NaCl, 1 mM DTT, 0.5% DMSO,0.15 g/mL purified membrane, and tritiated Compound 136 probe at Kd. Theprobe Kd was determined by titrating tritiated probe under the standardassay conditions plus and minus excess unlabeled probe and fitting theresulting data to a “One site —Total and nonspecific binding” model inGraphpad Prism, version 6.0, San Diego, Calif., US. Initially, 0.25 μlof compound dissolved in DMSO at varying concentrations was dispensed toa 384 well plate. Membrane and probe were both prepared at 2× theirfinal concentration in 1× assay buffer as described above. 25 μL ofmembrane was added to the wells and incubated for 10 minutes. 25 μL ofdiluted probe was then added to the wells. The assay was incubated for90 minutes at room temperature. The entire assay volume was thentransferred to Millipore GF/B 384-well plates pretreated with 15 μL 0.5%PEI. The filter plates were washed 3× with 75 μL 25 mM TRIS, ph 7.5,0.1% BSA and then dried overnight. Following addition of 45 μLUltimaGold scintillant, the samples were counted in a Perkin ElmerTopcount. The radioactivity remaining is a measure of bound probe. Fromthe bound probe vs concentration of compound titration curve, the IC50is determined by fitting the data to a standard 3 parameter IC50 modelusing either Graphpad Prism, version 6.0, San Diego, Calif., US, orusing GeneData Analyzer, Basel, Switzerland.

Example 10. WFS1 Knockout, Knockdown, and Over-Expression Studies 10A.Materials and Experiments Creation of Cells Stably Over-Expressing WFS1

WFS1 cDNA is amplified from clone RC202901 (Origene Technologies) withprimers 5′-TCC GCG GCC CCA AGC TTA TCG CCA TGG ACT CCA ACA CTG C-3′ (SEQID NO: 1), 5′-GAT GGG CCC AGA TCT CGA GTC AGG CCG CCG ACA GGA ATG-3′(SEQ ID NO: 2) and cloned into a retroviral mammalian expression vectorpCLPCX using HD Infusion (CLONTECH) at Hind3-XhoI sites using standardprocedures. The resulting clone is identified as pCLPCX_WFS1.

HEK293 (ATCC, catalog #CRL-1573) cells are plated in 10 cm dishes(Corning, product #430167) into 10 mL of complete DMEM cell culturemedia [DMEM (Life Technologies, product #11960-051) media supplementedwith 10% FBS (Hyclone, catalog #SH30071.03), antimycotic/antibiotic(Life Technologies, product #15240-062), and Glutamax (LifeTechnologies, product #35050-061)] at 3×10⁶ cells per dish. Cells areallowed to attach and grow overnight at 37° C. in humidified 5% CO₂.Cells are co-transfected with pVSV-G, pCMV-Gag/Pol and pCLPCX_WFS1 usingFugene 6 (Promega, catalog #E2691) according to manufacturer's protocol.Separately, cells are co-transfected with pVSV-G, pCMV-Gag/Pol andpCLPCX to produce control retrovirus. Cell culture media containingretrovirus (viral supernatant) is collected at 48 and 72 hours followingtransfection, filtered through a 0.4 uM filter, and stored at −80° C.

HEK293 cells are plated in 6 well plates (Corning, product #3516) in 2mL of complete DMEM cell culture media at 1×10⁵ cells well and allowedto attach and grow overnight at 37° C. in humidified 5% CO₂. Thefollowing day, the media is replaced with viral supernatant to which 10ug/ml of Polybrene® (Santa Cruz Biotech, catalog #sc-134220) is added.Viral supernatant is replaced 24 hours later with complete DMEM media.Transduced cells are selected in complete DMEM cell culture mediacontaining 1 microgram/mL of puromycin (Life Technologies, catalog#A1113803).

Creation of Cells with Stable Knockdown of WFS1

Colo-205 (ATCC, catalog #CCL-222), HepG2 (ATCC, catalog #HB-8065),CFPAC1 (ATCC, catalog #CRL-1918), or DU4475 (ATCC, catalog #HTB-123)cells are plated in 10 mL of complete DMEM cell culture media [DMEM(Life Technologies, product #11960-051) media supplemented with 10% FBS(Hyclone, catalog #SH30071.03), antimycotic/antibiotic (LifeTechnologies, product #15240-062), and Glutamax (Life Technologies,product #35050-061)] at 3×10⁶ cells per 10 cm cell culture plate(Corning, product #430167). Cells are allowed to attach and growovernight at 37° C. in humidified 5% CO2. Cells are transduced byaddition of 1×10⁶ infectious units of lentivirus encoding WFS1 shRNA(Santa Cruz Biotech, catalog #sc-61804-V) or a non-targeting controlshRNA (Santa Cruz Biotech, catalog #sc-108080) and 10 ug/ml ofPolybrene® (Santa Cruz Biotech, catalog #sc-134220) to the cell culturemedia. After 48 hours transduced cells are selected by the addition of 1microgram/mL of puromycin (Life Technologies, catalog #A1113803) to thecell culture media.

Creation of Cells with WFS1 Knockout by CRISPR/Cas9

A double cleavage strategy was employed to remove large fragments fromthe WFS1 locus. Suitable target sites in WFS1 exon 8 were first selectedusing CRISPR design software to rank suitable target sites andcomputationally predict off-target sites for each intended target. Sixtop guide RNA sequences are identified and screened for activity usingthe Surveyor Mutation Detection Kit (Integrated DNA Technologies). Then,the best 2 guide RNAs were cloned into GeneArt OFP CRISPR nucleasevectors (Thermofisher, Cat #A21174) separately and co-transfected intoHepG2 cells using nucleofection (4D Nucleofector X, Lonza). Cells weresorted by FACS 48 hrs later to enrich for the OFP positive cellpopulation. The OFP positive cell population were plated into 96-wellplates at 0.5-5 cells/well to isolate clonal cell lines. After allowingcells to expand for 2-3 weeks, plates were inspected for presence ofcolonies. When colonies became more than 70% confluent, they weredissociated with trypsin and were further expanded. Cell clones withhomozygous double cleavage of WFS1 exon 8 were detected with PCR andconfirmed with DNA sequencing.

Determination of Cellular WFS1 Protein Levels

Cell lysates are prepared either by whole cell lysis with cold LysisBuffer (20 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA,1% Triton, 2.5 mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mMNa3VO4, 1 μg/ml leupeptin, 0.05% SDS) or by membrane extraction usingMem-PER™ Plus Membrane Protein Extraction Kit (Life Technologies,catalog #89842). Protein content of cell lysates is determined using theBCA assay (Life Technologies Cat #23225). Twenty micrograms of proteinare loaded onto Nupage 3-8% TA gels (Life Technologies, catalog#EA0375BOX) and subjected to electrophoresis in Tris-Acetate SDS runningbuffer (Life Technologies, catalog #LA0041) approximately 1.5 hours.Protein is transferred to nitrocellulose membranes via wet transfer inTris-glycine transfer buffer (Life Technologies, catalog #LC3675)containing 0.2% SDS and 10% methanol. Nitrocellulose membranes wereblocked in Odyssey® blocking buffer (Li-Cor Bioscience, catalog#927-40000) for at least 1 hour. Wfs1 protein (i.e. wolframin) wasdetected by immunoblotting with anti-WFS1 antibody (Abcam, catalog#ab176909) diluted in Odyssey blocking buffer overnight at 4° C.Membranes were washed 3 times in TBST (50 mM Tris, 150 mM NaCl, 0.05%Tween 20) at room temperature and then immunoblotted with anti-rabbitantibody conjugated with IRDye 800 (Li-Cor Bioscience catalog#926-32211) for 1 hour at room temperature while rocking gently.Membranes were imaged on the ODYSSEY® CLx Imaging System (Li-CorBioscience). Wolframin has a predicted kDa of ˜110 kD.

Determination of Compound Effects on In Vitro Cell Viability

HEK293 cells containing empty pCLPCx vector (HEK293 empty), HEK293 cellsstably over-expression WFS1 (HEK293 WFS1), HepG2, and HepG2 cells whereWFS1 was depleted via CRISPR/Cas9 (HepG2 WFS1 KO) cells were plated into96-well black plates (Corning, product #3904) in 100 microliters ofcomplete DMEM cell culture media [DMEM (Life Technologies, product#11960-051) media supplemented with 10% FBS (Hyclone, catalog#SH30071.03), antimycotic/antibiotic (Life Technologies, product#15240-062), and Glutamax (Life Technologies, product #35050-061)] at1,000 (HEK293) or 5,000 (HepG2) cells per well. Cells were allowed toattach and grow overnight, after which compounds are added at variousconcentrations. Cell viability was assessed 96 hrs after compoundaddition with CellTiter-Glo reagent (Promega, catalog #G7570) accordingto manufacturer's protocol and measurement on a Pherastar luminescenceplate reader (BMG Labtech).

10B. Results and Discussions Knockout of WFS1 by CRISPR/Cas9 Blocks theAbility of Compounds to Cause Calcium Flux, Induce ER Stress Markers,Induce Global Gene Expression Changes, and Inhibit Cell Viability.

CRISPR/Cas9 was used to create HepG2 cells with a WFS1 gene deletion.Compared to parental HepG2 cells (FIG. 2, lane 1), HepG2 cells subjectedto WFS1 gene deletion (FIG. 2, lane 2) have a complete absence of WFS1protein expression. FIG. 2 also shows the presence of monomeric andmultimeric forms of WFS1, all of which are absent in the WFS1 genedeleted cells. There was no difference in tubulin protein levels betweenparental HepG2 and HepG2 WFS1 knockout cells (FIG. 2, lanes 1 and 2,respectively).

Compounds described herein showed induction of calcium flux, as shown inFIG. 5A and exemplified by induction of luciferase in HepG2 cellscontaining an XBP1-Luc reporter (Table 47). In order to determinewhether WFS1 is involved in compound induced calcium flux, parentalHepG2 cells and HepG2 cells with CRISPR/Cas9 mediated WFS1 knockout (KO)were subjected to increasing concentrations of Compound 136 andintracellular calcium levels were measured after 30 minutes of compoundaddition. Depletion of WFS1 from HepG2 cells completely eliminatedCompound 136 ability to induce calcium flux as compared to parentalHepG2 cells (FIG. 5A), suggesting WFS1 expression level relates to theability of the compounds to induce calcium flux.

Also, in order to determine whether WFS1 is involved in compound inducedER stress, parental HepG2 cells and HepG2 cells with CRISPR/Cas9mediated WFS1 knockout (KO) were exposed to Compound 136 or thapsigarginfor 6 hours after which time cell lysates were prepared and subjected toimmunoblotting. FIG. 6 shows that WFS1 depletion prevents the inductionof the ER stress marker proteins XBP1(s) and ATF4 by Compound 136. Incontrast, depletion of WFS1 had a much lesser effect on thapsigargin(thaps) induced XBP1(s) and ATF4. These results further indicate thatWFS1 expression level relates to the ability of the compounds to inducecalcium flux. Further, depletion of WFS1 from HepG2 cells preventedCompound 136 from causing changes in global gene expression after 6hours of exposure (FIG. 7). In contrast WFS1 depletion had no effect onthapsigargin induced changes in global gene expression (FIG. 7.)

To determine the effect of WFS1 depletion on compound mediatedinhibition of cell viability, parental HepG2 cells and HepG2 cells whereWFS1 was deleted by CRISPR/Cas9 were exposed to increasingconcentrations of either Compound 136 or Compound 253 for 96 hours afterwhich time viability was determined using Cell Titer Glo reagent(Promega). Depletion of WFS1 from HepG2 cells resulted in a greater than100 fold shift in IC50 for Compound 136 and a greater than 5 fold shiftin IC50 for Compound 253, suggesting that WFS1 is required for compoundsdescribed herein to inhibit cell viability (Table 47 and Table 48). TheIC50s for the viability of both the HepG2 parental and WFS1 knockoutcells are summarized in Table 47: A<0.5 μM; 0.5 μM≤B<2.0 μM; 2.0μM≤C<10.0 μM; D≥10.0 μM.

TABLE 48 Compound 136 Compound 253 Cell Line IC₅₀ (μM) IC₅₀ (μM) HepG2parental 0.33 A 0.64 B HepG2 WFS1 KO >27 D 4.4 C

To determine the effect of WFS1 over-expression on compound mediatedeffects on calcium flux and cell viability, Hek293 cells were transducedwith either an empty retroviral vector or a retroviral vector expressingfull length WFS1 cDNA. Hek293 cells transduced with the WFS1 encodingretrovirus expressed greater than 100 times the amount of WFS1 proteinthan empty vector Hek293 cells (FIG. 3). The effect of WFS1over-expression on the induction of calcium flux induced by Compound 136is shown in FIG. 5B. Over-expression of WFS1 resulted in approximately10 fold reduction in the EC50 of Compound 136, suggesting that WFS1 isinvolved in the mechanism of action for the compounds described herein.

Further, the effect of WFS1 over-expression on the inhibition of cellviability by Compounds 136 and 253 is shown in Table 49 (below).Over-expression of WFS1 in Hek293 cells results in greater than a 1000fold reduction in the IC50 of both of these of compounds, suggestingthat WFS1 alone is sufficient to impart sensitivity of non-respondercells to the compounds described herein. The IC50s for the viability ofboth the Hek293 empty vector and WFS1 over-expressing cells aresummarized in Table 47: A<0.06 μM; 0.06 μM≤B<0.6 μM; 0.6 μM≤C<3.0 μM;D≥3.0 μM.

TABLE 49 Compound 136 Compound 253 Cell Line IC₅₀ (μM) IC₅₀ (μM) Hek293empty vector >27 D 15 D Hek293 WFS1 over-expressor 0.03 A 0.012 A

Knockdown of WFS1 by RNAi Reduced Ability of Compounds to InhibitTCF/LEF Reporter Activity and Cell Viability

Transduction of HepG2 (FIG. 4), DU4475 (FIG. 4), and Colo-205 (notshown) cells with a lentivirus encoding a shRNA targeting WFS1 resultedin a greater than 75% reduction of WFS1 protein levels when compared tocells transduced with lentivirus encoding a non-targeting control shRNAas determined by immunoblot (FIG. 4). Stable knockdown of WFS1 proteinlevels in DU4475 and Colo-205 cells containing the TC-Luc reporterresulted in a 5 to 7 fold increase in the IC₅₀ for Compound 253 andCompound 136 in blocking TCF reporter activity as compared to controlcells (Table 50). Furthermore, knockdown of WFS1 protein levels inDU4475, Colo-205, and HepG2 cells resulted in a greater than 50 foldincrease in the IC₅₀ for Compound 253 and Compound 136 in reducing cellviability as compared to control cells (Table 51). These results suggestthat WFS1 is involved in the inhibition of TCF reporter activity andviability of the tested compounds.

TABLE 50 Expression of shRNA targeting WFS1 reduces ability of Compound253 and Compound 136 to inhibit TCF reporter activity. Compound 136Compound 253 Cell Line IC₅₀ ((μM) IC₅₀ ((μM) Colo-205 Control  0.1 +/−0.02 0.2 +/− 0.03 shRNA Colo-205 WFS1 0.7 +/− 0.2 1.5 +/− 0.7  shRNADU4475 Control 0.09 +/− 0.01 0.2 +/− 0.03 shRNA DU4475 WFS1 0.7 +/− 0.11.0 +/− 0.1  shRNA

TABLE 51 Expression of shRNA targeting WFS1 reduces ability of Compound253 and Compound 136 to inhibit cell viability. Compound 136 Compound253 Cell Line IC₅₀ (μM) IC₅₀ (μM) Colo-205 Control 0.05 +/− 0.02 0.14+/− 0.14 shRNA Colo-205 WFS1 >9.0 +/− 0    >9.0 +/− 0    shRNA DU4475Control 0.08 +/− 0.01  0.1 +/− 0.01 shRNA DU4475 WFS1 6.1 +/− 2.5 7.8+/− 2.3 shRNA HepG2 Control 0.26 0.20 shRNA HepG2 WFS1 2.2  17    shRNABinding Capacity of Compound 136 to Cellular Membrane ExtractsCorrelates with Levels of WFS1 Protein.

The binding affinity of radiolabeled Compound 136 to cell membranesderived from cells expressing different levels of WFS1 as determined byimmunoblotting is shown in FIG. 8. As the figure shows, the Bmax(pg/mol) of Compound 136 correlates with the level of WFS1 protein incellular membrane. This correlation is consistent with Compound 136 andthe compounds described herein directly binding to WFS1 or a WFS1associated complex or a protein complex in tight stoichiometry withWFS1.

Example 11. In Vivo Inhibition of TCF/LEF Reporter Activity in TumorsDetermination of Compound Effects on In Vivo Tumor TCF/LEF ReporterActivity

Colo205-TCF/LEF-Luciferase (Luc) tumor cells were expanded in completeDMEM cell culture media [DMEM (Life Technologies, product #11960-051)media supplemented with 10% FBS (Hyclone, catalog #SH30071.03),antimycotic/antibiotic (Life Technologies, product #15240-062), andGlutamax (Life Technologies, product #35050-061)] with 1 ug/mlpuromycin. After reaching confluency/high density, the loosely attachedcells in media were transferred from the flask to 50 ml conical tubes.Tumor cells adhered to plastic were detached with trypsin and combinedwith cells in the conical tubes. The tumor cells were triturated,counted, and pelleted by centrifugation. Cell pellets were resuspendedin 0.9% injectable saline (6×10{circumflex over ( )}7 cells/ml). A 50 ulvolume (3×10{circumflex over ( )}6 cells) was injected subcutaneously inthe flanks of 4-6 wk old female nu/nu mice (Charles River Laboratories).Approximately 13-16 days after implantation, tumors between 200-500mm{circumflex over ( )}3 were selected (based on caliper measurementsand applying the formula volume=width×length×0.54) and randomized intogroups of n=4. Mice were dosed by oral gavage with compound dissolved in1:3:5:1 EtOH:DMSO:PEG-400:H₂O at a rate of 10 ml/kg or 1:3:5:1EtOH:DMSO:PEG-400:H₂O alone (Vehicle Control). Tumors were collectedfrom mice euthanized by CO₂ inhalation and snap frozen in liquidnitrogen. Tumors were stored in a −80 degrees C. freezer until they wereprocessed.

Tumors were thawed on ice and homogenized in cold Lysis Buffer (20 mMTris-HCl (pH 7.5), 150 mM NaCl, 1 mM Na2EDTA, 1 mM EGTA, 1% Triton, 2.5mM sodium pyrophosphate, 1 mM beta-glycerophosphate, 1 mM Na3VO4, 1μg/ml leupeptin, 0.05% SDS) using a closed tissue grinder system (FisherScientific, Cat #02-542-09) on ice according to manufacturer'sinstructions. For 100 mg of tumor, 500 uL of Lysis Buffer was used.Tumor lysate was transferred to a pre-chilled microcentrifuge tube andcentrifuged at 10,000×g for 10 minutes at 4 degrees C. Supernatant wastransferred to a new pre-chilled microcentrifuge tube and was usedimmediately for analysis of protein content and luciferase activity.

Protein content of tumor lysate supernatant was determined using the BCAassay (Life Technologies Cat #23225). Luciferase activity of tumorlysate supernatant was determined by addition of Steady-Glo luminescencereagent (Promega, Cat #E2550) according to manufacturer's instructionsand measurement on a Pherastar luminescence plate reader (BMG Labtech).Luciferase activity was normalized to protein content.

The in vivo inhibition of TCF/LEF reporter activity in Colo-205 tumorsare summarized in Table 53.

TABLE 53 In Vivo Inhibition of TCF/LEF Reporter Activity in Colo-205Tumors. Percent Percent Percent Remaining Remaining Remaining ActivityActivity Activity at 8 at 8 at 8 Comp. hrs after Comp. hrs after Comp.hrs after # Dosing # Dosing # Dosing Comp 1 32% Comp 149 17% Comp 38414% Comp 4 23% Comp 324 16% Comp 385 25% Comp 42 20% Comp 332 51% Comp386 19% Comp 46 20% Comp 154 24% Comp 398 83% Comp 246 18% Comp 155 17%Comp 388 13% Comp 253 15% Comp 160 18% Comp 395 19% Comp 272 14% Comp335 18% Comp 396 23% Comp 77 30% Comp 174 22% Comp 397 23% Comp 80 34%Comp 186 23% Comp 257 30% Comp 122 16% Comp 207 18% Comp 383 36% Comp136 24% Comp 377 33% Comp 188 15% Comp 14 33% Comp 223 39% Comp 63  9%Comp 135 43% Comp 229 49% Comp 409 27% Comp 414 27% Comp 416 22% Comp420 28% Comp 421 23% Comp 423 70% Comp 425 29% Comp 431 29% Comp 434 26%Comp 436 16% Comp 437 20% Comp 443 100%  Comp 445 98% Comp 447 76% Comp449 22% Comp 450 32% Comp 455 63% Comp 466 101%  Comp 491 41% Comp 49617% Comp 499 31% Comp 500 43% Comp 501 53% Comp 511 52% Comp 513 90%Comp 517 93% Comp 518 21% Comp 522 91% Comp 528 28% Comp 542 22% Comp545 51% Comp 549 30% Comp 551 20% Comp 556 62% Comp 557 20% Comp 565 68%Comp 578 47% Comp 589 94% Comp 602 57% Comp 643 22% Comp 656 51% Comp658 62% Comp 678 75%

Example 12. In Vivo Efficacy

Female immune deficient mice (Charles River, 4-6 wks age) wereanesthetized with Ketamine-Xylazine (140 mg/kg-14 mg/kg ip) and shaved.Puralube eye ointment was applied to the eyes to prevent desiccation ofthe corneas. Betadine and 7000 ethanol was applied to the shavedlocation to sterilize the skin at the location of the incision. Theanimals were placed in a biosafety cabinet for the duration of thesurgery. Using scissors, an 8 to 10 mm incision was made in the lateralflank of the skin. A tumor fragment weighing between 50 and 150 mg wasplaced under the skin at the incision site using forceps, and stapleswere used to close the incision. The staples were removed 5 to 7 daysafter surgery. Starting approximately two weeks after implantation,animals were weighed, and tumors were measured using caliper twiceweekly. Tumor volume was calculated using the formula:volume=length×width{circumflex over ( )}2×0.52.

Compound administration began when xenografts reached approximately100-300 mm3 and continued until control xenografts reached 10% of theanimal's body weight. Test compounds were administered orally by gastricgavage. Percent tumor growth inhibition (% TGI) was calculated on theindicated treatment day. Percent TGI is defined as: [1-(del T/delC)]×100%, where del T is the final minus initial average volumes of thetreated group, and del C is the final minus initial average volumes ofthe control group. Table 54 shows efficacies of multiple testingcompounds against the non-small cell lung cancer (NSCLC) adenocarcinomaline OD33966 in nu/nu mice. The tested compounds were administeredorally. Vehicle control consisted of either 0.5% methylcellulose/0.1%sodium lauryl sulfate or 20% captisol. Tumor volumes were determined bycaliper measurement twice a week.

TABLE 54 In vivo efficacy for the NSCLC Patient Derived XenograftOD33966 Compound # Dose Treatment day % TGI* Compound 1 200 mpk bid 1994.53 Compound 42 100 mpk qd 14 79.63 Compound 46 100 mpk qd 14 93.26Compound 246 100 mpk qd 11 82.57 Compound 253 100 mpk qd 14 96.60Compound 272 100 mpk qd 14 77.91 Compound 77 100 mpk qd 14 98.45Compound 83 100 mpk qd 14 97.25 Compound 94 100 mpk qd 14 94.52 Compound136 100 mpk qd 14 106.65 Compound 405 100 mpk qd 12 91.03 Compound 403100 mpk qd 12 102.84 *[1-(del T/del C)] × 100%

Table 55 shows efficacy of Compound 136 against various tumorXenograftmodels. As shown in Table 55, Compound 136 inhibits growth of tumorxenografts derived from multiple cancer types. Tumors were engrafted ineither SCTD or nude mice. Compound 136 was administered orally once aday (QD) at 100 mg/kg. Vehicle control consisted of 0.500methylcellulose/0.1% sodium lauryl sulfate. Tumor volumes weredetermined by caliper measurement twice a week. TGL: tumor growthinhibition at end of treatment. CR: complete regression (majorityresponse on treatment is that tumors become undetectable), PR: partialregression (majority response on treatment is that tumors shrink by atleast 330%).

TABLE 55 In vivo efficacy of Compound 136 in various tumor XenograftsBody weight Treat- change at Model ment end of Tumor type name duration% TGI* treatment Multiple myeloma NCI-H929 21 days >100% (CR) +1.8%Multiple myeloma OPM2 21 days >100% (CR) −0.9% Non-small cell OD33966 21days >100% (PR) +4.5% lung Non-small cell OD26749 21 days >100% (CR)−0.1% lung Non-small cell LXFL 625 21 days >100% (CR) +3.7% lungNon-small cell LXFL 529 21 days >100% (CR) +5.5% lung Non-small cellLXFL 2207 21 days >100% (PR) +1.5% lung Breast DU4475 14 days 99%Melanoma MEXF 1765 21 days >100% (CR) +9.8% Bladder BXF 1036 21days >100% (PR) +5.5% Kidney RXF 631 21 days 89% +6.2%

Example 13. Assessment of Monotherapy Response in Multiple Panels ofCancer Cell Lines

This study was performed to identify candidate gene expression markerswhich could predict in vitro response to Compound 136.

TABLE 56 Abbreviations Abbreviation Term AML Acute myeloid leukemiaATPlite Adenosine triphosphate luciferase BH Benjamini-Hochberg DNADeoxyribonucleic acid FDR False discovery rate GI Growth inhibitionNSCLC Non-small cell lung cancer CORID Oncology responder ID

Materials

TABLE 57 Bladder cancer cell line list CELL LINE TUMOR TYPE 5637 BladderT-24 Bladder RT4 Bladder RT-112 Bladder J82 Bladder SCaBER BladderHT-1197 Bladder SW780 Bladder UM-UC-3 Bladder TCCSUP Bladder

TABLE 58 428 Cancer Cell Line List CELL LINE TUMOR TYPE 22RV1 prostate5637 bladder 59M ovary 769-P kidney 786-0 kidney A101D skin A2058 skinA253 head/neck A2780 ovary A3/KAW DLBCL A375 skin A4-Fuk DLBCL A498kidney A549 NSCLC A673 bone A704 kidney ACC-MESO-1 mesothelioma ACHNkidney AGS gastric AN3-CA endometrium AsPC-1 pancreas AU565 breast BENNSCLC BICR 16 head/neck BICR 22 head/neck BICR 31 head/neck BICR 56head/neck BT-20 breast BT-474 breast BT-549 breast BxPC-3 pancreasC2BBe1 colorectal C32 skin C3A liver CA46 burkitt lymphoma Caki-1 kidneyCAKI-2 kidney CAL-120 breast CAL-12T NSCLC CAL-148 breast CAL-27head/neck CAL-54 kidney CAL-85-1 breast Calu-1 NSCLC Calu-3 NSCLC Calu-6NSCLC CAMA-1 breast Caov-3 ovary Caov-4 ovary CAPAN-2 pancreas CCK-81colorectal CCRF-CEM T cell ALL CEM-C1 T cell ALL CESS AML CFPAC-1pancreas ChaGo-K-1 NSCLC CHL-1 skin CHP-126 neuroblastoma CHP-212neuroblastoma CJM skin CL-11 colorectal CL-34 colorectal CL-40colorectal COLO-201 colorectal COLO-205 colorectal COLO-320 colorectalCOLO-320-DM colorectal COLO-320-HSR colorectal COLO-668 SCLC COLO-677multiple myeloma COLO-678 colorectal COLO-679 skin COLO-684 endometriumCOLO-699 skin COLO-741 colorectal COLO-783 skin COLO-792 skin COLO-800skin COLO-818 skin COLO-829 skin COLO-849 skin COLO-858 skin COR-L105NSCLC COR-L23 NSCLC COV362 ovary COV644 ovary CW-2 colorectal Daoymedulloblastoma Daudi burkitt lymphoma DB DLBCL DBTRG-05MG gliomaDetroit562 head/neck DK-MG glioma DLD-1 colorectal DMS-114 SCLC DMS-273SCLC DU-145 prostate DU-4475 breast DV-90 NSCLC EBC-1 NSCLC EC-GI-10esophageal ECC10 gastric EFO-21 ovary EFO-27 ovary EPLC-272H NSCLC FaDuhead/neck FTC-238 thyroid G-361 skin G-401 soft tissue G-402 soft tissueGA-10 burkitt lymphoma GCIY gastric GSS gastric H4 glioma H9 cutaneous Tcell lymphoma HARA NSCLC HCC1438 NSCLC HCC2157 breast HCT-116 colorectalHCT-15 colorectal HEC-1 endometrium HEC-1-A endometrium HEC-1-Bendometrium HEC-151 endometrium HEC-251 endometrium HEC-265 endometriumHEC-50B endometrium HEC-59 endometrium HEL92.1.7 AML Hep 3B 2.1-7 liverHep G2 liver Hey-A8 ovary HGC-27 gastric HH cutaneous T cell lymphomaHL-60 AML HLC-1 NSCLC HLE liver HLF liver HMC-1-8 NSCLC HMCB skin HOP-62NSCLC HPAF-II pancreas HRT-18G colorectal Hs 294T skin Hs 739.T breastHs 746T gastric Hs 852.T skin HSC-2 head/neck HSC-3 head/neck HSC-4head/neck HT-144 skin HT-29 colorectal HuCCT1 bile duct HuH-1 liverHuH-28 bile duct HUH-6-clone5 liver HuH-7 liver HuNS1 multiple myelomaHuP-T3 pancreas HUTU-80 gastric IA-LM NSCLC IGR-1 skin IGR-37 skinIGR-39 skin IGROV-1 ovary IM-95 gastric INA-6 multiple myeloma Ishikawaendometrium IST-MES1 mesothelioma IST-MES2 mesothelioma IST-SL2 SCLC JARendometrium Jeko-1 mantle cell lymphoma JHH-1 liver JHH-2 liver JHH-5liver JHH-6 liver JHH-7 liver JHOC-5 ovary JHOS-2 ovary JHUEM-1endometrium JHUEM-2 endometrium JHUEM-3 endometrium JHUEM-7 endometriumJIMT-1 breast JL-1 mesothelioma JM1 B cell lymphoma JU77 mesotheliomaJVM-2 mantle cell lymphoma K-562 CML KASUMI-1 AML KATO III gastric KE-39gastric KE-97 multiple myeloma KELLY neuroblastoma KG-1 AML Ki-JK ALCLKLE endometrium KLM-1 pancreas KMM-1 multiple myeloma KMS-11 multiplemyeloma KMS-20 multiple myeloma KMS-34 multiple myeloma KNS-62 NSCLCKNS-81 glioma KP-2 pancreas KP-3 pancreas KP-4 pancreas KP-N-SI9sneuroblastoma KS-1 glioma KYM-1 soft tissue KYSE-180 esophageal KYSE-30esophageal KYSE-510 esophageal KYSE-70 esophageal LC-1sq NSCLCLCLC-97TM1 NSCLC Li-7 liver LK-2 NSCLC LMSU gastric LO68 mesotheliomaLOU-NH91 NSCLC LoVo colorectal LS-123 colorectal LS-411N colorectalLS-513 colorectal LU-134-A SCLC LU-135 SCLC LU-65 NSCLC LU-99 NSCLCLUDLU-1 NSCLC LXF-289 NSCLC MC116 B cell lymphoma MCAS ovary MCF7 breastMDA-MB-175-VII breast MDA-MB-231 breast MDA-MB-361 breast MDA-MB-435Sskin MDA-MB-436 breast MDA-MB-453 breast MDA-MB-468 breast MEL-JUSO skinMES-SA endometrium MeWo skin MFE-280 endometrium MFE-296 endometriumMG-63 bone MIA PaCa-2 pancreas Mino mantle cell lymphoma MKN1 gastricMKN45 gastric MKN7 gastric MKN74 gastric MM.1S multiple myeloma MOLT-4 Tcell ALL Molt3 T cell ALL MOR-CPR NSCLC MPP-89 mesothelioma MSTO-211Hmesothelioma MV-4-11 AML Namalwa burkitt lymphoma NB1 neuroblastomaNCC-StC-K140 gastric NCI-H292 NSCLC NCI-H322 NSCLC NCI-H345 SCLCNCI-H446 SCLC NCI-H460 NSCLC NCI-H520 NSCLC NCI-H596 NSCLC NCI-H69 SCLCNCI-H747 colorectal NCI-H929 multiple myeloma NCI-SNU-1 gastric NH-6neuroblastoma NU-DHL-1-epst DLBCL NUGC-3 gastric NUGC-4 gastric OAW-42ovary OC-316 ovary OCUM-1 gastric ONS-76 medulloblastoma OV56 ovary OV90ovary OVCAR-3 ovary OVCAR-4 ovary OVCAR-5 ovary OVCAR-8 ovary OVISEovary OVSAHO ovary OVTOKO ovary PA-1 Ovary PANC-08-13 pancreas Pane02.03 pancreas Pane 02.13 pancreas Pane 03.27 pancreas Pane 04.03pancreas Pane 05.04 pancreas PC-3 prostate PCM6 multiple myelomaPE-CA-PJ15 head/neck PE-CA-PJ41-cl D2 head/neck Pfeiffer DLBCL PK-1pancreas PK-45H pancreas PLC/PRF/5 liver PSN1 pancreas Raji burkittlymphoma RCM-1 colorectal REC-1 mantle cell lymphoma REH B cell ALLRERF-GC-1B gastric RERF-LC-Ad2 NSCLC RERF-LC-AI NSCLC RERF-LC-MS NSCLCRH-41 soft tissue RKO colorectal RL non-Hodgkins B cell lymphoma RL95-2endometrium RPMI-7951 skin RPMI-8226 multiple myeloma RS4-11 B cell ALLRT4 bladder RVH-421 skin SBC-5 SCLC SC-1 non-Hodgkins B cell lymphomaSCC-15 head/neck SF126 glioma SH-10-TC gastric SH-4 skin SHP-77 SCLCSJSA-1 bone SK-BR-3 breast SK-HEP-1 liver SK-LU-1 NSCLC SK-MEL-1 skinSK-MEL-24 skin SK-MEL-28 skin SK-MEL-3 skin SK-MEL-30 skin SK-MEL-31skin SK-MEL-5 skin SK-MES-1 NSCLC SK-N-AS neuroblastoma SK-N-BE-2neuroblastoma SK-N-DZ neuroblastoma SK-N-FI neuroblastoma SK-OV-3 ovarySNB-75 glioma SNG-II endometrium SNG-M endometrium SNU-1197 colorectalSNU-16 gastric SNU-175 colorectal SNU-182 liver SNU-283 colorectalSNU-308 bile duct SNU-324 pancreas SNU-387 liver SNU-398 liver SNU-407colorectal SNU-423 liver SNU-449 liver SNU-478 bile duct SNU-620 gastricSNU-685 endometrium SNU-8 ovary SNU-81 colorectal SNU-878 liver SNU-C2Bcolorectal SNU-C4 colorectal SNU-C5 colorectal SU-DHL-1-epst ALCLSU-DHL-10-epst DLBCL SU-DHL-16-epst non-Hodgkins B cell lymphomaSU-DHL-2-epst B cell lymphoma SU-DHL-5-epst DLBCL SU-DHL-7-epst DLBCLSU-DHL-8-epst DLBCL SU.86.86 pancreas SUIT-2 pancreas SUM159PT breastSUP-B15 B cell ALL SUP-T1 T cell ALL SW1088 glioma SW1116 colorectalSW1271 SCLC SW1417 colorectal SW1573 NSCLC SW1990 pancreas SW48colorectal SW480 colorectal SW579 Thyroid SW620 colorectal SW756endometrium SW837 colorectal SW900 NSCLC SW948 colorectal T-24 bladderT3M-10 NSCLC T3M-4 pancreas T47D breast TCCSUP bladder TE-10 esophagealTE-11 esophageal TE-14 esophageal TE-159.T soft tissue TE-4 esophagealTE-5 esophageal TE-6 esophageal TE-8 esophageal TE-9 esophageal TENendometrium Toledo DLBCL TOV-21G ovary U-2-OS bone U-87 MG glioma U266B1multiple myeloma UWB1.289 ovary VMRC-LCD NSCLC WM-115 skin WM-266-4 skinWSU-FSCCL non-Hodgkins B cell lymphoma YD-10B head/neck YD-38 head/neckYH-13 glioma YMB-1 breast

Cell Culture Methods

Cells were removed from liquid nitrogen storage, thawed and expanded inappropriate growth media. Once expanded, cells were seeded in 384-welltissue culture treated plates at 500 cells per well. After 24 hours,cells were treated for either 0 hours or treated for 96 hours withCompound 136 (at the concentrations of 100 nM and 2 uM). At the end ofeither 0 hours or 96 hours, cell status was analyzed using ATPLite(Perkin Elmer) to assess the biological response of cells to drugcombinations.

Growth Inhibition

In this study, growth inhibition (GI) was used as the primary endpoint.ATP monitoring was performed using ATPLite, which allows for themonitoring of cytocidal, cytostatic and proliferative effects of drugson cells.

a. Univariate Gene Expression Analysis

Analyses of the transcript expression level and synergy valuecorrelations were undertaken in both an unbiased and biased manner. Theunbiased course involved choosing any genes with p values less than 0.06or 0.1 after multiple test correction. Other genes were added in abiased manner, taking into consideration biological function andrelationship to relevant pathways.

I. Results The Association Between WFS1 Gene Expression and Response toCompound 136

The relationship between WFS1 gene expression and response to Compound136 was evaluated in a panel of 9 bladder cancer cell lines (Table 57).Response to Compound 136 was associated with response (FIG. 9) and theassociation was statistically significant (Spearman rho 0.68, p-value0.048).

In addition, the relationship between response to Compound 136 andresponse was further assessed in a panel of 428 cancer cell lines (Table58). As expected, WFS1 gene expression was associated with response toCompound 136 at 2 μM (FIG. 10) and this association was statisticallysignificant (Spearman rho 0.42, p value 0.0056).

Finally, an in vivo study was run to evaluate the relationship betweenWFS1 expression in patient derived xenografts (PDX). To do this, the 10lung PDX models with the highest WFS1 gene expression and the 10 lungPDX models with the lowest WFS1 gene expression were selected from theOncotest compendium. There was a strong association between WFS1 geneexpression and response to Compound 136 in PDX models (FIG. 11).

CONCLUSIONS

WFS1 was predictive of response to Compound 136 as a single agent incancer cell lines and in patient-derived xenografts. The WFS1expression/Compound response relationship was held in the experimentsusing PDX model systems.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

All references provided herein are incorporated herein in its entiretyby reference. As used herein, all abbreviations, symbols and conventionsare consistent with those used in the contemporary scientificliterature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manualfor Authors and Editors, 2nd Ed., Washington, D.C.: American ChemicalSociety, 1997.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ring A isselected from a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, indanyl, a 4-8 membered saturatedor partially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, a8-12 membered saturated or partially unsaturated bicyclic heterocyclicring having 1-2 heteroatoms independently selected from nitrogen,oxygen, or sulfur, a 5-8 membered saturated or partially unsaturatedbridged bicyclic carbocyclic ring, a 5-6 membered monocyclicheteroaromatic ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromaticring having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur; L is a covalent bond or a C₁₋₆ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D)₂-, —C(F)₂—,—N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—,—N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—,—S(O)—, —S(O)₂—, or —Si(R)₂—, wherein -Cy- is an optionally substitutedbivalent group selected from phenylenyl, cyclopropylenyl,cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, furylenyl,tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl, piperidylenyl,triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl,2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl; R¹ ishydrogen; each of R² and R^(2′) is independently hydrogen, R^(D), or anoptionally substituted group selected from C₁₋₆ aliphatic, a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring,a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromaticring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur; or R² and R^(2′) are optionally taken together toform ═CH₂ or ═CH—(C₁₋₃ aliphatic); R³ is hydrogen, R^(D), or anoptionally substituted C₁₋₆ aliphatic group; or R⁴ is R^(D), —CD₂OH, oran optionally substituted C₁₋₃ aliphatic group; R⁵ is hydrogen, —C(O)R,—C(O)OR, —C(O)NR₂, an optionally substituted 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring, or a C₁₋₃ aliphaticgroup; each of R⁶ is independently halogen, —CN, —NO₂, —C(O)R, —C(O)OR,—C(O)NR₂, —NR₂, —NRC(O)R, —NRC(O)OR, —NRS(O)₂R, —OR, —P(O)R₂, —SR, —SF₅,—S(CF₃)₅, —S(O)R, —S(O)₂R, —S(O)(NH)R, —C(═NR)—OR, —O—C(═NR)—R, or R; ortwo R⁶ groups are optionally taken together to form ═O; each R isindependently hydrogen or an optionally substituted group selected fromC₁₋₆ aliphatic, a 3-8 membered saturated or partially unsaturatedmonocyclic carbocyclic ring, phenyl, a 4-8 membered saturated orpartially unsaturated monocyclic heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, ora 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur; two R groups onthe same nitrogen are optionally taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen and sulfur, optionallysubstituted with 1-2 oxo groups; R^(D) is a C₁₋₄ aliphatic group whereinone or more hydrogens are replaced by deuterium; X is N or CH; and n is0, 1, 2, 3, 4 or 5
 2. The compound of claim 1, wherein Ring A is a 3-8membered saturated or partially unsaturated monocyclic carbocyclic ring.3. The compound of claim 1, wherein Ring A is phenyl.
 4. The compound ofclaim 1, wherein Ring A is a 4-8 membered saturated or partiallyunsaturated monocyclic heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.
 5. The compoundof claim 1, wherein Ring A is a 5-6 membered monocyclic heteroaromaticring having 1-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.
 6. The compound of claim 1, wherein Ring A is


7. The compound of claim 1, wherein L is a C₁₋₆ bivalent straight orbranched saturated or unsaturated hydrocarbon chain wherein one to threemethylene units of the chain are independently and optionally replacedwith -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D)₂-, —C(F)₂—,—N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—,—N(R)C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—,—S(O)—, —S(O)₂—, or —Si(R)₂—.
 8. The compound of claim 1, wherein L is acovalent bond.
 9. The compound of claim 1, wherein L is a C₁₋₆ bivalentstraight or branched saturated or unsaturated hydrocarbon chain whereinone to three methylene units of the chain are independently andoptionally replaced with -Cy-, —O—, —C(R)₂—, —CH(R)—, —CH(OR)—,—CR(OR)—, —C(D)₂-, —C(F)₂—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —C(O)—,—OC(O)—, or —C(O)O.
 10. The compound of claim 9, wherein -Cy- is anoptionally substituted bivalent group selected from cyclopropylenyl,cyclobutylenyl, cyclopentylenyl, or cyclohexylenyl.
 11. The compound ofclaim 9, wherein -Cy- is an optionally substituted bivalent groupselected from furylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl,pyridylenyl, or thiazolylenyl.
 12. The compound of claim 1, wherein eachof R² and R^(2′) is independently hydrogen, R^(D), or an optionallysubstituted group selected from C₁₋₆ aliphatic, a 3-8 membered saturatedor partially unsaturated monocyclic carbocyclic ring, or a 4-8 memberedsaturated or partially unsaturated monocyclic heterocyclic ring having1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.13-15. (canceled)
 16. The compound of claim 1, wherein R² and R^(2′)taken together form ═CHCH₃.
 17. The compound of claim 1, wherein R² isC₁₋₆ aliphatic substituted by 1-3 halogen, —OH, —OCH₃, or —OC(CH₃)₃. 18.The compound of claim 1, wherein R² is a 3-8 membered saturated orpartially unsaturated monocyclic carbocyclic ring substituted by 1-3halogen, —OH, —OCH₃, or —OC(CH₃)₃.
 19. The compound of claim 1, whereinR² is a 4-8 membered saturated or partially unsaturated monocyclicheterocyclic ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, substituted by 1-3 halogen, —OH, —OCH₃, or—OC(CH₃)₃.
 20. The compound of claim 1, wherein R² is unsubstituted C₁₋₆aliphatic.
 21. The compound of claim 1, wherein R³ is hydrogen or anoptionally substituted C₁₋₆ aliphatic group.
 22. The compound of claim1, wherein R³ is C₁₋₆ aliphatic substituted by

or OCH₃.
 23. (canceled)
 24. The compound of claim 1, wherein R⁵ ishydrogen, —C(O)R, —C(O)OR, or a C₁₋₃ aliphatic group.
 25. The compoundof claim 1, wherein R⁵ is a 3-8 membered saturated or partiallyunsaturated monocyclic carbocyclic ring.
 26. The compound of claim 1,wherein R⁵ is


27. The compound of claim 1, wherein each of R⁶ is independentlyhalogen, —CN, —NO₂, —C(O)R, —C(O)OR, —C(O)NR₂, —NR₂, —NRC(O)R,—NRC(O)OR, —NRS(O)₂R, —OR, —P(O)R₂, —SR, —S(O)R, —S(O)₂R, —S(O)(NH)R, orR.
 28. The compound of claim 1, wherein one or more R⁶ is —NR₂.
 29. Thecompound of claim 28, wherein each R of the —NR₂ group is independentlyoptionally substituted C₁₋₆ aliphatic.
 30. The compound of claim 29,wherein each R of the —NR₂ group is independently


31. The compound of claim 1, wherein one or more R⁶ is —C(═NR)—OR. 32.The compound of claim 31, wherein the one or more R⁶ is—C(═NH)—OC(CH₃)₃.
 33. The compound of claim 1, wherein one or more R⁶ is—NO₂.
 34. The compound of claim 1, wherein one or more R⁶ is C₁₋₆aliphatic substituted by 1-5 halogen or —OH.
 35. The compound of claim1, wherein one or more R⁶ is —C(O)—R.
 36. The compound of claim 35,wherein the one or more R⁶ is —C(O)—CH₂OCH₂CF₃ or —C(O)—CH₂CH₂OCH₂CF₃.37. The compound of claim 1, wherein X is N.
 38. The compound of claim1, wherein n is 1, 2, 3, 4 or
 5. 39. The compound of claim 1, wherein Xis N, R³ is methyl, R⁴ is methyl, and R⁵ is hydrogen.
 40. The compoundof claim 1, of one of formula VI-a, VI-b, VI-c, or VI-d:

or a pharmaceutically acceptable salt thereof.
 41. (canceled)
 42. Thecompound of claim 40, wherein: R² is unsubstituted C₁₋₆ aliphatic, orR^(D);

 wherein one of R⁶ is —CF₃; n′ is 1, 2, 3, or 4; and n″ is 1, 2, or 3;or

 wherein n′″ is 0, 1, 2, or
 3. 43. The compound of claim 42, wherein R²is —CH₃, —CH₂CH₃, or —CH(CH₃) wherein one or more hydrogens areoptionally replaced by deuterium. 44-45. (canceled)
 46. The compound ofclaim 42, wherein

47-50. (canceled)
 51. A pharmaceutical composition comprising thecompound of claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier, adjuvant, or vehicle.
 52. Amethod for treating a cellular proliferative disorder in a patient, orfor inducing ER stress in a patient, or for inducing the unfoldedprotein response (UPR) in a patient, or for causing calcium release fromthe endoplasmic reticulum (ER) via a putative Ca2+ channel known asWolframin (WFS1) in a patient, comprising administering to said patientthe compound of claim 1, or a pharmaceutical composition thereof. 53-59.(canceled)
 60. The compound of claim 1, wherein L is:


61. The compound of claim 1, where L is:


62. The compound of claim 1, wherein L is:


63. The compound of claim 1, wherein L is:


64. The compound of claim 1, wherein L is:


65. The compound of claim 1, wherein L is:


66. The compound of claim 1, wherein L is: